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Abu Dhabi Stem Cells Center and Yas Clinic first in UAE to receive AABB accreditation for haematopoietic progenitor cell collection  Abu Dhabi Media Office

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Abstract

Induced pluripotent stem (iPS) cells are laboratory-produced cells that combine the biological advantages of somatic adult and stem cells for cell-based therapy. The reprogramming of cells, such as fibroblasts, to an embryonic stem cell-like state is done by the ectopic expression of transcription factors responsible for generating embryonic stem cell properties. These primary factors are octamer-binding transcription factor 4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Krppel-like factor 4 (Klf4), and the proto-oncogene protein homolog of avian myelocytomatosis (c-Myc). The somatic cells can be easily obtained from the patient who will be subjected to cellular therapy and be reprogrammed to acquire the necessary high plasticity of embryonic stem cells. These cells have no ethical limitations involved, as in the case of embryonic stem cells, and display minimal immunological rejection risks after transplant. Currently, several clinical trials are in progress, most of them in phase I or II. Still, some inherent risks, such as chromosomal instability, insertional tumors, and teratoma formation, must be overcome to reach full clinical translation. However, with the clinical trials and extensive basic research studying the biology of these cells, a promising future for human cell-based therapies using iPS cells seems to be increasingly clear and close.

Keywords: induced pluripotent stem cells, regeneration, cellular therapy, stem cells, muscular dystrophy

Stem cells can be classified as totipotent, pluripotent, or multipotent cells according to their biological source and the capacity to differentiate into other cell types. Totipotent stem cells are found very early in embryonal development and can differentiate into all cell types in the organism, as well as into extraembryonic tissues. Pluripotent cells can be isolated from blastocysts or the umbilical cord immediately after birth, and are also able to differentiate into all tissue cells, except extraembryonic structures. However, certain disadvantages must be observed when considering these stem cells in regenerative medicine. These include the high risk of rejection and ethical issues when the isolation is performed from embryos. On the other hand, due to their high plasticity, pluripotent stem cells are considered ideal to obtaining the multiple cell types required after stem cell-based therapies.

Multipotent stem cells are isolated from adult tissues and have no ethical issues involved. These include hematopoietic, mesenchymal, and neural stem cells. Multipotent stem cells can be isolated from the patients subjected to treatment, with no risk of rejection, and be expanded in vitro for transplant. However, these cells display reduced plasticity, as they can only differentiate into specialized cell types present in specific tissues or organs, their main disadvantage. The ideal cellular population best suited for stem cell-based therapies should combine the high plasticity of embryonic stem cells and the convenient isolation from patients under treatment. To this end, induced pluripotent stem (iPS) cells were generated using embryonic or adult somatic cells. The somatic cells are subjected to the ectopic expression of transcription factors that induce the stem cell-like properties and the high plasticity required for cell therapy. Therefore, iPS cells can potentially revolutionize the field of regenerative medicine and provide new tools for stem cell research.

In the nineties, it was demonstrated that somatic cells could be reprogrammed to an undifferentiated state by transferring their nuclear content into unfertilized oocytes [1]. These results showed that cellular differentiation is reversible. Later, the resetting of a somatic epigenotype to a totipotent state was successfully achieved when adult thymocytes were fused with embryonic stem cells [2]. These and other pioneering studies [3] paved the way for the Nobel prize-awarded paper published by Takahashi and Yamanaka [4], who hypothesized that factors that play important roles in the maintenance of embryonic stem cell identity also play pivotal roles in the induction of pluripotency in somatic cells. In this study, mouse embryonic and adult fibroblasts were genetically reprogrammed to a pluripotent state, and the authors coined the term iPS cells. These cells were generated by using a retrovirus-based gene transfer system carrying the octamer-binding transcription factor 4 (Oct3/4), sex determining region Y-box 2 (Sox2), Krppel-like factor 4 (Klf4), and c-Myc transcription factors, all involved in pluripotency maintenance in embryonic stem cells [4].

IPS cell technology brings great promise to medicine, such as personalized cell therapy, disease modeling, and new drug development and screening. However, some challenges must be circumvented, such as reprogramming efficiency and the risks associated with chromosomal instability, insertional tumor development, and teratoma formation. In this context, here, we review the literature, present the main methods of cell reprogramming, and show some initial results of clinical tests. Besides, we discuss the possibility of applying iPS cells in the treatment of muscular dystrophies.

Various delivery methods have been used to insert reprogramming factors into somatic cells. These approaches can be divided into integrative, which involves the insertion of exogenous genetic material into the host genome, and non-integrative methods. The integrative systems include the use of viral vectors (lentivirus, retrovirus, and inducible or excisable retro or lentivirus) and non-viral vectors (linear or plasmid DNA fragments and transposons). Likewise, non-integrative systems include viral (Sendai virus and adenovirus) and non-viral vectors (episomal DNA vectors, RNAs, human artificial chromosomes (HAC), proteins, and small molecule compounds) [5,6] (Figure 1 and Table 1).

Somatic Cells Reprogramming Methods. The methods used to produce iPS cells can be classified into integrative viral, such as retrovirus (a), lentivirus (b), or inducible retro or lentivirus (c); and integrative non-viral, such as linear or circular DNA fragments (d) or transposons (e). In regards to non-integrative methods, they can also be separated as viral, such as adenovirus (f) or Sendai virus (g). Non-integrating non-viral methods are episomal DNA (h), RNAs (i), human artificial chromosome (HAC) (j), proteins (k), or small molecules (compounds) (l). The red DNA represents epigenetic inserted sequences for cellular reprogramming.

Comparison of multiple reprogramming techniques.

The expression of primarily just four transcription factors (c-Myc, Klf4, Oct4, and Sox2) is sufficient to reprogram somatic cells into a pluripotent state. The discovery of those factors related to the embryonic stem cell phenotype allowed the production of embryonic stem-like cells first from mouse embryonic and adult murine fibroblasts [4] and then from adult human dermal fibroblasts [7,8]. The Oct4 seems to be the most important reprogramming factor, whereas Klf4 and c-Myc can be replaced by Nanog and Lin28, for example [9].

The first experiments achieved the conversion of somatic cells into iPS cells using retroviral or lentiviral transduction of the transcription factors. However, these vectors become integrated into the cell genome and represent a risk of insertional mutagenesis [10]. Moreover, they may leave residual transgene sequences as part of the host genome, leading to unpredictable alterations in the phenotype of downstream applications. To reduce multiple proviral integrations of the transcription factors and to increase the efficiency of the retrovirus- or lentivirus-based reprogramming process, polycistronic RNA viral vectors were created. These constructs allowed the expression of all reprogramming factors driven by a single promoter, reducing the number of genomic insertions [11]. Once the integration of the reprogramming factors is achieved, it is also essential to control the extent of expression. To this end, the use of excisable Cre-loxP technology for site-specific recombination and inducible tetracycline- or doxycycline-based vector systems allowed greater control of inserted genes expression, reducing inefficient silencing and uncontrolled reactivation [5].

It is important to highlight that other factors have been described as being able to induce cellular pluripotency and self-renewal. Besides, several types of somatic cells have also been subjected to in vitro reprogramming, such as pancreatic cells, neural stem cells, stomach and liver cells, mature B lymphocytes, melanocytes, adipose stem cells, and keratinocytes. These results are summarized in the review published by Oldole and Fakoya [5].

The integrative non-viral technologies used to obtain iPS cells are based on the transference of DNA sequences using liposomes or electroporation [5], for example. It was possible to reprogram both mouse and human fibroblasts using a single multiprotein expression vector comprising the coding sequences of c-Myc, Klf4, Oct4, and Sox2 linked with 2A peptide [24]. When this single vector-based reprogramming system was combined with a piggyBac transposon, the authors successfully established reprogrammed human cell lines from embryonic fibroblasts with sustained pluripotency markers expression. PiggyBac is a mobile genetic element that includes a transposase enzyme that mediates gene transfer by targeted insertion and excision in the DNA. Moreover, Woltjen and collaborators showed the efficient reprogramming of murine and human embryonic fibroblasts using doxycycline-inducible transcription factors delivered by PiggyBac transposition. The authors also showed that the individual PiggyBac insertions could be removed from the iPS cell lines [15], being completely excised from its integration site in the original DNA sequence [25], which is a significant advantage.

The integrative methods for random or site-specific DNA insertion can affect normal cell function and physiology, including the transformation for tumorigenic cells, proliferation, and apoptosis control. Therefore, non-integrating viral vectors were constructed to generate iPS cells, the most promising of which is the Sendai virus, a negative-strand RNA virus [26]. The Sendai virus has the advantage of being an RNA virus that does not enter the nucleus and can produce large amounts of proteins [27]. Adenoviruses are also non-integrating viruses that appear to be excellent expression vehicles to generate iPS cells. They show DNA demethylation (a characteristic of reprogrammed cells), express endogenous pluripotency genes, and can generate multiple cells and tissues. However, the reprogramming efficiency of adenoviral vectors is only 0.001%0.0001% in mouse [28] and 0.0002% in human cells [29], several orders of magnitude lower, when compared to lentiviruses or retroviruses [5]. The use of viruses, even in non-integrating systems, requires refined steps to exclude reprogrammed cells with active replicating viruses. Moreover, viral vectors may elicit an innate and adaptive immune response against viral antigens after the transplant to patients. In this case, the transplanted cells would become the target of molecular and cellular cytotoxic pathways, directly compromising the engraftment and therapy success.

Non-integrating non-viral systems include the transient expression of reprogramming factors inserted as combined episomal minicircles or plasmids. These contain the complementary DNA (cDNA) of Oct3/4, Sox2, and Klf4 and another plasmid containing the c-Myc cDNA, for example. This technique resulted in iPS cells with no evidence of plasmid integration [16], suggesting that episomal plasmids may be the best option for clinical translation. This technique has already been used in the autologous induced stem cell-derived retinal treatment for macular degeneration [30]. Moreover, minicircle vectors are also used as a method for cellular reprogramming and consist of minimal vectors containing only the eukaryotic promoter and the cDNA(s) that will be expressed. This technique was able to reprogram human adipose stromal cells, but the reprogramming efficiency is substantially lower (~0.005%) when compared to lentiviral-based techniques, for example [31].

HACs are also non-integrative systems for gene delivery with the main advantage of being able to transfer multiple genes and large sequences, which can be combined with sequences that increase therapy security and expression control. The authors constructed two different HACs, and the reprogramming of mouse embryonic fibroblasts into iPS cells was better achieved when the artificial chromosome also encoded a p53-knockdown cassette. The iPS cells were uniformly generated, and a built-in safeguard system was included, consisting of a reintroduced HAC encoding the Herpes Simplex virus thymidine kinase, which allowed the targeted elimination of reprogrammed cells by ganciclovir treatment [19].

Another promising strategy focusing on non-integrative non-viral reprogramming methods for iPS cell generation is through RNA molecules, such as micro-RNAs. These sequences are small endogenous non-coding RNAs that play important post-transcriptional regulatory roles [32]. They also repress gene expression through translational inhibition or by promoting the degradation of mRNAs [33]. One study showed that normal human hair follicles could be reprogramed into human iPS cells via doxycycline-inducible pTet-On-tTS vectors inserted by electroporation. These constructs contained pre-microRNA members of the miR-302 cluster, including pre-miR-302a, 302b, 302c, and 302d [34]. Although the reprogramming efficiency was not reported in this study, it is known that iPS cells induced by micro-RNAs have a reprogramming efficiency above 10% and also have the lowest tumorigenicity rate. Although this approach has not yet been used in any clinical test, it may help in future developments in regenerative medicine [33]. More recently, micro-RNAs were used in combination with other reprogramming methods to increase reprogramming efficiency [5].

Another promising transgene-free approach is the direct mRNA transfection of synthetic modified coding sequences of the Yamanaka factors (c-Myc, Klf4, Oct4, and Sox2). This is a non-integrating method that can reprogram multiple human cell types to pluripotency very efficiently, avoiding the antiviral immune response. The authors further showed that the same technology efficiently directed the differentiation of RNA-induced pluripotent stem cells (RiPSCs) into terminally differentiated myogenic cells [35]. The method of the direct delivery of synthetically transcribed mRNAs triggered somatic cell reprogramming with higher efficiency when compared to retroviruses [35]. These mRNAs are commercially available, and the authors used cationic lipid delivery vehicles for transfection in cell culture for seven days [27]. Similar alternatives are emerging as the cellular introduction of all reprogramming factors via a single synthetic polycistronic RNA replicon that requires single transfection [36]. In this case, the transfection of adult fibroblasts resulted in an efficient generation of iPS cells with the expression of all stem cell markers tested, consistent global gene expression profile, and in vivo pluripotency for all three germ layers.

Transgene-free cellular reprogramming has also been achieved using recombinant proteins. In this case, the generation of stable iPS cells was possible by directly delivering the four reprogramming proteins fused with a cell-penetrating peptide [22]. However, it has been technically challenging to synthesize large amounts of bioactive proteins that can cross the plasma membrane. This problem associated with low efficiency shows that much remains to be done for the use of recombinant proteins as a viable method. Two research groups were able to make enough bioactive proteins in an E. coli expression system and to reprogram mouse [37] and human fibroblasts [22]. More recently, Weltner and collaborators also used Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 nuclease (CRISPR-Cas9)-based gene activation (CRISPRa) for reprogramming human skin fibroblasts into iPS cells [38]. CRISPR/Cas9 is a genome-editing tool powered by the design principle of the guide RNA that targets Cas9 to the desired DNA locus and by the high specificity and efficiency of CRISPR/Cas9-generated DNA breaks [39].

Another system for cellular reprogramming to generate iPS cells was the use of small-molecule compounds, which was developed by Hou and collaborators [23]. These authors used a combination of seven small molecules, but the efficiency achieved was only 0.2%. Small molecules have some advantages such as structural versatility, reasonable cost, easy handling, and no immune response. They can boost the application of iPS cells in disease therapy and drug screening. Some of these chemical compounds are valproic acid, trichostatin A (TSA), and 5-azacytidine, all capable of enhancing iPS cell generation [40]. One of the main advantages is that small (chemical) molecules can stimulate endogenous human cells to make tissue repair and regeneration in vivo, with no ectopic expression of factors. On the other hand, the method is time-consuming, and there is still a risk of genetic instability [6] to be overcome in future studies.

Despite all developments in the field of iPS cells, viral vector-based methods remain most popular among researchers [41]. Still, non-integrating non-viral self-excising vectors are more likely to be clinically applicable. To select an iPS cell reprogramming method, it is essential to maximize the capacity of cellular expansion in vitro, validate the detection and removal of incompletely differentiated cells, and search for genomic and epigenetic alterations. Probably, different somatic cell types will require different reprogramming methods to differentiate into the required terminal cell type in vivo.

Regardless of the reprogramming method, the risk of teratoma formation is inherent to iPS cells, as residual undifferentiated pluripotent cells retain very high plasticity. Although this risk has been reduced by highly sensitive methods for detecting remaining undifferentiated cells, teratoma formation cannot be ruled out [42]. Besides, c-Myc, one of the factors used for cellular reprogramming, is a well-known proto-oncogene, and its reactivation can give rise to transgene-driven tumor formation [43].

IPS cells can differentiate into cells from any of the three primary germ layers [44], with great potential for clinical applications. Neurodegenerative disorders, for example, and diseases in which in vitro differentiation and transplant protocols have been established using conventional embryonic stem cells, are areas of immediate interest for iPS-based cell therapy. IPS cell lines can be generated in virtually unlimited numbers from patients affected by diseases of known or unknown causes. These cells can differentiate in vitro into the disease-affected cell type and offer an opportunity to gain insight into the disease mechanism to identify novel disease-specific drugs. In Table 2, we show examples of iPS cells generated from patients with sporadic or genetic diseases.

Examples of terminally differentiated cells generated from induced pluripotent stem (iPS) cells.

Some drugs that are in clinical trials were derived from iPS cell studies. For example, cardiomyocyte-derived iPS cells obtained from patients with type-2 long QT syndrome were used to test the efficacy and potency of new and existing drugs [51]. In regenerative medicine, iPS cells can be used for tissue repair or replacement of injured tissues after cell transplantation. Early trials using iPS cell transplantation focused on age-related macular degeneration, and this is a refractory ocular disease that causes severe deterioration in the central vision due to senescence in the retinal pigment epithelium (RPE). Preclinical studies showed good results in various animal models and corroborated the first clinical trial that began in 2014 [54]. Kamao and collaborators generated human iPS cells derived from RPE (hiPSC-RPE) cells that met clinical use requirements, including cellular quality and quantity, reproducibility, and safety. After the transplant, autologous non-human primate iPSC-RPE cell sheets showed no immune rejection or tumor formation [55]. Then, in the clinical trial using iPS cells, the cells were generated from skin fibroblasts obtained from patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. In this test, autologous iPS cell-based therapy did not cause any significant adverse event [30]. However, the test with the second patient was discontinued due to genetic aberrations detected in the autologous iPS cells. With the rapid progress of genomic technologies, genetic aberrations in iPS cells will probably be reduced to a minimal level, with technological advances also focusing on automated closed culture systems [56].

Recent advances in genome editing technology have made it possible to repair genetic mutations in iPS cell lines derived from patients. Special attention has recently been focused on organoids derived from iPS cells, which are three-dimensional cellular structures mimicking part of the organization and functions of organs or tissues. Organoids were generated for various organs from both mouse and human stem cells, generating intestinal, renal, brain, and retinal structures, as well as liver organoid-like tissues, named liver buds [57]. Therefore, iPS cells-derived organoids can also be useful for drug testing and in vitro studies based on more complex cell models.

Moreover, iPS cells derived from cancer cells (cancer-iPS cells) can be a novel strategy for studying cancer. Primary cancer cells have been reprogrammed into iPS cells or at least to a pluripotent state, allowing the study and elucidation of some of the molecular mechanisms associated with cancer progression [58].

The possibility of using iPS cells in the treatment of various diseases has brought hope regarding their potential to treat an increasing number of conditions. As iPS cells can be differentiated into all different cell types, new prospects for studying diseases and developing treatments by regenerative medicine and drug screening have emerged. Therefore, a large number of clinical and preclinical trials are being carried out [59] to treat human diseases using iPS cells.

The reprogramming of somatic cells was demonstrated using different animal species, including mouse, rat [60], dog [61], a variety of non-human primate species [62], pig [63], horse [64], cow [65], goat [66], and sheep [67]. However, once the goal of pre-clinical trials is the clinical use of iPS cells, a number of these trials are being conducted using human iPS cells. For specific applications, however, human cells are expected to be rejected by the animal hosts, and immunosuppressive protocols are required for long-term observation. On the other hand, immunomodulating drugs may affect the disease phenotype, and careful planning of every step is necessary. Any stem-cell-based clinical trial must follow all precedents already established for the evaluation of small biological molecules or human tissue remodeling and must be safe and effective. The production of cells must be carried out in facilities that follow the current Good Manufacturing Practices (GMP) and have stringent quality control for reagents with well-defined product release and potency assays. GMP is a set of conditions that define the principles and details of the manufacturing process, quality control, evaluations, and documentation for a particular product. Moreover, the best delivery system of iPS cells must be evaluated for each disease, which can be the use of intravascular catheters or surgical injection, for example.

Human-derived iPS cell lines successfully repopulated the murine cirrhotic liver tissue with hepatic cells at various differentiation stages. They also secreted human-specific liver proteins into mouse blood at concentrations comparable to those of proteins secreted by human primary hepatocytes [68]. In other preclinical studies, iPS cells were generated using adult dsRed mouse dermal fibroblasts via retroviral induction, following transplantation into the eye of immune-compromised retinal degenerative mice. After thirty-three days of differentiation, a large proportion of the cells expressed the retinal progenitor cell marker Pax6 and photoreceptor markers. Therefore, adult fibroblast-derived iPS cells are a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease [69]. IPS cells were also generated from nonobese diabetic mouse embryonic fibroblasts or nonobese diabetic mouse pancreas-derived epithelial cells and differentiated into functional pancreatic beta cells. The differentiated cells expressed diverse pancreatic beta-cell markers and released insulin in response to glucose and KCl stimulation. Moreover, the engrafted cells responded to glucose levels by secreting insulin, thereby normalizing blood glucose levels, showing that these cells may be an important tool to help in the treatment of diabetic patients [70]. Human cardiomyocytes derived from iPS cells are another source of cells capable of inducing myocardial regeneration for the recovery of cardiac function. These cells were established using human dermal fibroblasts transfected with a retrovirus carrying the conventional factors Oct3/4, Sox2, Klf4, and c-Myc. When the iPS cells were transplanted into the myocardial infarcted area in a porcine model of ischemic cardiomyopathy, the activation of WNT signaling pathways induced cardiomyogenic differentiation. It was also observed that the transplanted cells significantly improved cardiac function and attenuated left ventricular remodeling [71]. In another study, dopaminergic neurons derived from protein-induced human iPS cells exhibited gene expression, physiology, and electrophysiological properties similar to the dopaminergic neurons found in the midbrain. The transplantation of these cells significantly rescued the motor deficits of rats with striatal lesions, an experimental model of Parkinsons disease [72]. Moreover, after stroke-induced brain damage, adult human fibroblast-derived iPS cells were transplanted into the cortical lesion and, one week after the transplantation, there was the initial recovery of the forepaw movements. Moreover, engrafted cells exhibited electrophysiological properties of mature neurons and received synaptic input from host neurons [73].

In October 2018, 2.4 million iPS cells reprogrammed into dopaminergic precursor cell neurons were implanted into the brain of a patient in his 50s. In the three-hour procedure, the team deposited the cells into twelve sites, known to be centers of dopamine activity. The patient showed no significant adverse effects [74]. The first allogeneic clinical trial using iPS cells derived from mesenchymal stem cells for the treatment of graft-versus-host disease has also been reported, and no treatment-related serious adverse effects were observed [75]. Other clinical studies using iPS cells are being conducted in patients with heart failure [76,77]. Moreover, other tests have been approved for neural precursor cells for spinal cord injuries [78] and corneal epithelial cell sheets for corneal epithelial stem cell deficiency [79]. Thus, ongoing clinical tests provide a better understanding of clinical aspects involving immunosuppressants and fundamental elements such as genomic data that will pave the way for therapies using iPS cells.

The iPS cells have the potential to revolutionize the field of neurodegenerative diseases, which are characterized by the progressive deterioration of neuronal function. Therefore, multiple capacities are affected, leading to cognitive impairment, memory deficits, deficiency in motor function, loss of sensitivity, dysfunction of the autonomous brain system, changes in perception, and mood [80]. Among neurodegenerative diseases, Alzheimers disease is the most prevalent form of dementia, characterized by the accumulation of amyloid-beta (A) plaques and Tau-laden neurofibrillary tangles. Tau is a microtubule-associated protein found in the axons of the nerve cells, and these aggregates and tangles are the histopathological hallmarks of the disease [81]. The dysfunction and degeneration of neurons indeed underlie much of the observed decline in cognitive function, but various other types of non-neuronal cells are increasingly being implicated in the disease progression [82]. Therefore, iPS cells are emerging as an invaluable tool to better modeling the complex interactions that occur between multiple cell types in vivo. 3D and co-culture systems of iPS-derived cells in vitro hold promise to better understand the relevance of multiple cell types and the pathomechanisms that underlie the disease progression. Therefore, iPS cells have been generated from patients and healthy donors to study multiple genetic mutations in neurons, astrocytes, oligodendrocytes, microglia, pericytes, and vascular endothelial cells [83]. Moreover, a mutant Tau model derived from iPS cells was generated and showed several phenotypes associated with this neurodegenerative disease, including the pathogenic accumulation of Tau for drug screening [84]. Choi et al., 2014 showed a 3D culture model based on iPS cells that histopathologically reproduces the hallmarks of Alzheimers disease, including a robust extracellular deposition of A. This model was sensitive to drugs, which reversed the pathological phenotype [85]. The use of neural models derived from iPS cells can validate molecular mechanisms identified in the disease models in rodents, for example, and play an important role in the discovery and screening of new drugs [86].

Parkinsons disease is another important disease; being the second most common neurodegenerative disorder, it affects 2% to 3% of the population over 65 years of age. Characteristic features of Parkinsons disease include neuronal loss in specific areas of the substantia nigra and widespread intracellular protein (-synuclein) accumulation [87]. Due to the loss of dopaminergic neurons in localized regions of the brain, the use of human cells for therapeutic purposes has been studied with special attention. These assessments include iPS cells, whose good results supported the deployment of some studies that are already in the clinical phase. Pre-clinical studies have shown the efficient generation of iPS cells-derived dopaminergic motor neurons from non-human primates. Then, these cells were efficiently transplanted into a model of Parkinsons disease in rats [88]. Several new protocols have improved the efficiency of obtaining dopaminergic neurons from iPS cells for the study and modeling of Parkinsons disease [89]. The iPS cells used in some studies were mainly from patients carrying mutations in synuclein alpha, leucine-rich repeat kinase 2, PTEN-induced putative kinase 1, parkin RBR E3 ubiquitin-protein ligase, cytoplasmic protein sorting 35, and variants in glucosidase beta acid [90]. Although improvements are still needed, iPS cells make it possible to develop patient-specific disease models using disease-relevant cell types. Interestingly, using a human iPS cells-derived model of Parkinsons disease, it was found that the myocyte enhancer factor 2C-peroxisome proliferator-activated receptor- coactivator-1 (MEF2C-PGC1) pathway may be a new therapeutic target for Parkinsons disease. The data from this study provided mechanistic insight into geneenvironmental interaction in the pathogenesis of the disease [91]. Thus, it is important to develop models of neurodegenerative diseases using iPS cells because they involve a complex interplay of genetic alterations, transcriptional feedback, and endogenous control by transcription factors. Probably, the combination of different experimental approaches, using cellular systems and animal models, will increase the successful translation to the clinical practice [92].

In a successful pre-clinical study, the authors demonstrated that human dopaminergic neurons generated from iPS cells, and transplanted into a primate model of Parkinsons disease, established connections with the host monkey brain cells with no tumor formation after two years [93]. Immediately after the successful animal experiments, the Japanese research group implanted reprogrammed stem cells into the brain of a patient with Parkinsons disease for the first time in 2018 (as NEWS Reported by Nature https://www.nature.com/articles/d41586-018-07407-9).

Recently, extracellular vesicles/exosomes derived from iPS cells of different lineages were involved in neurological diseases. Extracellular vesicles are lipid-enclosed structures with a diameter of 301000 nm, carrying transmembrane and cytosolic proteins. Exosomes are a subset of extracellular vesicles, with a diameter ranging between 30 and 200 nm. Functionally, they play an important role in intercellular communications, immune modulation, senescence, proliferation, and differentiation in various biological processes, and are vital in maintaining tissue homeostasis [94]. On the other hand, and as cited before, abnormal protein aggregation has been implicated in many neurodegenerative processes that lead to human neurological disorders. Recent reports suggested that exosomes combine these two important characteristics, as they are involved in the intercellular transfer of macromolecules, such as proteins and RNAs, and seem to play an important role in the aggregate transmission among neurons [95]. The authors showed that extracellular vesicles from iPS cells carry proteins and mRNA that can induce or maintain pluripotency, which can be used in regenerative strategies for neural tissue [96]. If this is true, extracellular vesicles/exosomes derived from corrected iPS cells, which do not accumulate protein aggregates, may be safer for human treatment than iPS cells themselves [94]. The infusion of neuronal exosomes into the brains of a murine model of Alzheimers disease decreased the A peptide and amyloid depositions [97]. Moreover, exosomes obtained from stem cells were able to rescue dopaminergic neurons from apoptosis [98]. The authors showed that extracellular vesicles from mesenchymal stem cells, when injected into a mouse model of Alzheimers disease, reduced the A plaque burden and the number of dystrophic neurites in the cortex and hippocampus [99]. Extracellular vesicles were also derived from human iPS neural stem cells and used for stroke treatment [100]. The results using extracellular vesicles/exosomes obtained from iPS cells point to a promising future in the treatment of neurodegenerative diseases.

Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem) [101]. The terminal pathology often shows muscle fibers necrosis and muscle tissue replacement by fibrotic or adipose tissues. Currently, there is no cure for MD, and the available treatments are palliative or of limited effectiveness [102]. The most frequent and one of the most severe forms of all MD is the Duchenne muscular dystrophy (DMD), a muscle pathology caused by the lack of the protein dystrophin. In this case, previous cell-based therapies did not show satisfactory results after myoblast transplantation [103]. Myoblasts are the progeny of muscle satellite cells (SC), the main stem cell population found in adult skeletal muscles. Quiescent SCs are triggered to reenter into the cell cycle mainly by muscle damage, and the SC-derived myoblasts proliferate and fuse to form new multinucleated myofibers [101]. In most myoblast-based therapies, allogeneic cells were obtained from muscle biopsies from healthy donors, resulting in transplanted cell rejection by the immune system, with low surviving rates, poor dispersion, and differentiation [103,104,105]. With the advances of iPS cell technology, some of these issues are being addressed (Figure 2).

iPS cells in Duchene muscular dystrophy cell therapy. The somatic cells derived from specific patients with Duchenne muscular dystrophy (DMD) can be reprogrammed into iPS cells with reprogramming factors. These cells are then genetically corrected to express the protein dystrophin for the autologous muscular injection of muscle-committed cells.

One of the main problems in the application of stem cell therapy in muscle diseases is to obtain large numbers of cells for sufficient engraftment, and the use of iPS cells may overcome this obstacle. For this purpose, Darabi and colleagues [106] applied the conditional expression of Pax7 to iPS cells, a transcription factor that plays a role in SC proliferation. Then, Pax7+ iPS cells were obtained on a larger scale for transplant into a mouse dystrophic muscle, which showed dystrophin+ fibers with superior strength [106]. Moreover, the authors genetically restored the dystrophin expression in autologous iPS cells derived from DMD patients. For this, three corrective methods were used, which were exon knock-in, exon skipping, and frameshifting, and the exon knock-in was the most effective approach [107]. The Cas9 protein (CRISPR-associated protein 9), derived from type II CRISPR (clustered regularly interspaced short palindromic repeats) bacterial immune systems, is a technology that has also emerged as an approach capable of targeting the mutated dystrophin gene, aiming to rescue its expression in vitro in iPS cells derived from selected patients [108].

Moreover, using CRISPR-Cas9 technology with single guide RNA, dystrophin expression was restored by exon skipping through myoediting in iPS cells. The genetic alterations observed in the multiple patients included large deletions, point mutations, or duplications within the DMD gene. The corrected iPS cells efficiently restored the expression of dystrophin and the corresponding mechanical contraction force in derived cardiomyocytes [109]. In summary, several methods of gene editing have been applied for the correction of the DMD gene to allow the transplantation of genetically corrected autologous iPS cells. Of these, the CRISPR-Cas9 system, in particular, has passed multiple proof-of-principle tests and is now being used in pre-clinical trials (Figure 2).

Reprogrammed fibroblast- and myoblast-derived iPS cells were also obtained from patients with limb-girdle muscular dystrophy type 2D (LGMD2D). This disease is a sarcoglycanopathy caused by mutations in the SCGA gene, which provides instructions for making the alpha component of the sarcoglycan protein complex. This multiprotein complex plays a role in the anchoring of the dystrophin-glycoprotein complex (DGC) to the extracellular matrix and helps to maintain muscle fiber membrane integrity. The iPS cells were expanded and genetically corrected in vitro with a lentiviral vector carrying the human gene encoding the -sarcoglycan. Finally, the transplantation of mouse iPS cells into -sarcoglycan-null immunodeficient mice, an experimental model of the disease, resulted in the amelioration of the dystrophic phenotype [110]. This transplant also showed that iPS cells restored the compartment of SC, an essential checkpoint for sustained muscle regeneration.

Recently, Perepelina and collaborators generated iPS cells from EmeryDreifuss muscle dystrophy associated with the genetic variant LMNAp.Arg527Pro. Patient-specific peripheral blood mononuclear cells were reprogrammed using the Sendai virus system, and the authors comment that this is a useful tool to study laminopathies in vitro [111]. Moreover, using three-dimensional (3D) tissue engineering techniques, artificial skeletal muscle tissue was generated using iPS cells from patients with Duchenne, limb-girdle, or congenital muscular dystrophies [112]. In this way, artificial muscles recapitulated characteristics of human skeletal muscle tissue, providing an invaluable tool to study pathological mechanisms, drug testing, cell therapy, and the development of tissue replacement protocols.

The use of iPS cells still has many challenges ahead before they can be clinically used in the supportive treatment of patients with MD. Among these, we can cite the injection of iPS cells (or muscle-committed iPS-derived cells) into large muscles, the immunological recognition of proteins expressed only after the genetic correction, the capacity of cellular dispersion through the muscle, the number of therapeutic interventions needed to replenish cellular muscle populations, the ability to produce corrected SC for sustained muscle recovery, and the control of transplanted cells death.

To address these and other limitations, we propose that autologous iPS cells be submitted to multiple treatments aiming to improve cellular engraftment and clinical use. Besides the genetic correction of underlying pathological mutations, these cells can be further treated in culture to boost cell proliferation, long-term survival, dispersion in the muscle, differentiation into muscle fibers, and others. We proposed before the use of multiple combined in vitro treatments for adoptively transferred myoblasts for cell-based therapy, and these are summarized in [101]. These treatments include vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF), Wnt7a, Ursolic acid, and extracellular matrix components. Moreover, the recipient muscle to be injected with the corrected and boosted iPS cells can also be treated to favor the engraftment. These treatments include actinin receptor type 2B inhibitor, IL-6, JAK/STAT 3 inhibitor, growth factors, the coinjection of other supportive cell types, such as macrophages and fibroblasts, and others.

We believe that the correct choice for the ideal combination of the cell type to be reprogrammed into iPS cells, the technical procedure for genetic correction, the in vitro treatments to boost iPS cells, and the in vivo preparation of recipients muscles, hold the key for a more successful application of iPS cells in clinical translation. However, we believe that systemic treatments consisting of the injection of cells will not lead to individual muscle damage and strength improvement. The transplanted cells do not express the required repertoire of molecules necessary for endothelial transmigration. Probably, selected individual and more affected muscles are more likely to benefit from cellular-based therapies, followed by treatments that can increase injected cell dispersion within the muscle.

Currently, publicprivate partnership consortia are providing resources to form iPS cell banks for clinical and research purposes. These banks have coordinated standards to meet international criteria for quality-controlled repositories of iPS cells. Although the use of iPS cells for autologous therapy seems more appropriate, having allogeneic banks of iPS cells already generated and tested would reduce the time needed to start treatment, decrease costs, and increase the chances of recovery of treated individuals [113]. Thus, although many technical challenges must still be overcome, the technology of iPS cells has already taken a marked leap in clinical management and in vitro models to study and treat diseases.

D.G.B.: manuscript preparation and review; S.I.H.: manuscript review and preparation of figure; C.M.C.: manuscript preparation; L.A.A.: manuscript review and figure preparation; A.H.-P.: manuscript and figure preparation and review. All authors have read and agreed to the published version of the manuscript.

This work was funded by CNPq (Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico) grant numbers 407711/2012-0 and 421803/2017-7 and Fundao Oswaldo Cruz.

The authors declare no conflict of interest.

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Induced Pluripotent Stem Cells: Hope in the Treatment of Diseases ...

IPS Cell Therapy Comments Off on Induced Pluripotent Stem Cells: Hope in the Treatment of Diseases … | March 11th, 2025

What are possible side effects of stem cell therapy ? Patients often reach out to ask about such risks They usually refer to unproven stem cell clinics.

Todays post addresses the scope of stem cell therapy side effects and risks based on available hard data. Its also important to discuss possible unknown risks.

Stem cell risks at unproven clinics | Why do stem cells pose risks | Tumors| Impact of lab growth | Infections | Blood clots | MSCs |Other risks | Intranasal stem cells and exosomes | References

In this post I am focusing on the risks primarily associated with unproven stem cell clinics. Not for established methods like bone marrow transplantation, which have their own risks including the shared one of infection.

Recent publications in journals have helped clarify risks. This literature includes a study by my UC Davis colleague Gerhard Bauer and a special report by The Pew Charitable Trust. Gerhards paper presents the types of side effects that appear more common after people go to stem cell clinics. After closely following this area for a decade I was familiar with many of the examples of problems.

One of the highest profile examples of bad outcomes was the case where three people lost their vision due to stem cells injected by a clinic.

I have included a YouTube video below on stem cell therapy side effects as well.

Why do stem cells pose risks?

One major reason is that stem cells are uniquely powerful cells.

By definition they can both make more of themselves and turn into at least one other kind of specialized cells. This latter attribute is called potency and the process of becoming other cells is called differentiation. The ability to make more of themselves is called self-renewal.

The most powerful stem cells are totipotent stem cells that can literally make any kind of differentiated cell. The fertilized human egg is the best example of a cell having totipotency. The first few cell divisions after that retain the totipotency. Next in the power lineup are pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). These cells are not directly used in therapies.

Adult stem cells are multipotent, which means they can make just a few types of specialized cells.

What is the best type of stem cell? The best type of stem cell depends on the condition that is trying to be treated and may not be the most powerful.

In any case, the power of stem cells is one reason they also pose risks along with mishandling that can cause infections. Stem cells are not always easy to control and misdirected power can do harm.

Let me explain and start with the side effect that seems most concerning to most people but is probably the rarest. Tumor formation.

If someone injects a patient with stem cells, its possible that the self-renewal power of stem cells just wont get shut off. In that scenario, the stem cells could drive the formation of a tumor.

Why wouldnt a transplanted stem cell always eventually hit the brakes on self-renewal? It could be that the stem cell has one or more mutations. For any stem cells grown in a lab, within the population of millions of cells in a dish, there are going to be at least a few with mutations that crop up. Thats just the way it goes with growing cells in a lab. The longer you grow them the more mutations they will have on average.

Even stem cells not grown in the lab have the same spectrum of mutations as the person they were isolated from. It may seem odd to think about, but we all have some mutations.

Research suggests it takes more than one cell with cancer-causing potential to make a tumor in experiments in the lab, but in actual people, we just dont know. Many cancers may arise from one stem cell gone awry. If a clinic injects 100 or 500 million cells, a one-in-a-million rate of potentially dangerous cells means that 100-500 such risky cells end up in the patient. The risk of getting an actual tumor may still be low but I wouldnt take those odds.

The encouraging news here is that the incidence of tumors in stem cell clinic customers, particularly in the U.S., appears extremely low.

The odds of getting a tumor are far lower for cells never grown in a lab but its still possible. Oddly, receiving someone elses stem cells (we call this allogeneic) might pose a lower cancer risk because your immune system is going to see those cells as foreign from the start. Itll reject them. Still, an immunocompromised state could play a role.

Some stem cells, especially those with mutations, might be able to somewhat fly under the radar of the immune system to some extent. This could allow them to grow into a tumor.

The Pew report does a nice job of summarizing risks and there are several reports of tumors.

The possibility of infections after stem cell injections is another risk that is often discussed. Infections from injections of stem cells or other biologics are probably the most common type of side effect. Bacteria can sometimes already be in the product that is injected. Or germs can be introduced by poor injection or preparation methods by the one doing the procedure.

The distributor Liveyon had a product contaminated with bacteria that sickened at least a dozen people who were hospitalized. Some of them ended up in the ICU. A few may even have permanent issues.

Infection risk usually does not arise from the cells themselves.

Another risk is the potential for blood clots.

In the case of adipose biologics life SVF, they mostly consist of a mixture of a dozen or so other kinds of cells found in fat. Fat cells just live in fat so they arent supposed to be floating around in your blood. As a result, after IV injection, many fat cells are thought to get killed right away by the immune system or the microenvironment. While in the blood, fat and other stromal-type cells, whether dead or alive, may catalyze clot formation, which is dangerous.

Some of these cells end up landing in the lungs. There many cells are probably being killed and theres also risk of blood clot formation.

Unproven clinics mainly sell MSCs.

MSCs could have some powerful uses in medicine. I can already see a few rigorous clinical trials that look exciting.

However, the way some unproven clinics use MSCs can be highly risky.

Such cells just shouldnt be injected willy-nilly into dozens of places in patients including into peoples eyes. Further, what are called MSCs by some unproven clinics may also not meet even basic lab standards and may not have the potential of other MSC preps. Some such clinic preps are likely just fibroblasts or mostly dead cells.

MSCs produced in a rigorous manner in clean labs by experienced teams are likely to be a far superior product than that typically made by just any strip mall clinic. I dont endorse any cell therapy clinic selling MSCs at this time, but some are doing far better than others. They do research and publish papers.

Properly conducted injections of unmodified, high quality MSC-type cells or marrow cells into joints or for other orthopedic conditions by qualified providers in theory should pose almost zero risk of pulmonary emboli or cancer. Clinics using excellent procedures and cell products also should pose a very low risk of infection, a risk more similar to getting medical procedures in general even unrelated to stem cells.

Overall, Im not sure I believe such MSCs even from the best clinics can provide lasting benefit for diverse orthopedic conditions, but the overall risks associated with them should be quite low there relatively speaking.

Patients have also asked me about other potential risks of cell injections.

I wrote a post about possible graft versus host disease in stem cell recipients. This would only happen in people receiving someone elses stem cells and probably only with IV administration. Its not clear if GvHD is something that happens to patients after going to clinics selling allogeneic cells. With no immunosuppression, it should be highly unlikely.

Beyond outright tumor formation, it is also possible that stem cells may become an undesired or even dangerous tissue type that isnt technically an actual tumor. The example that comes to mind is the practice mentioned earlier of some clinics injecting fat cells into peoples eyes. What seems to have happened in some cases is that the mesenchymal cells (MSCs) or other cells like fibroblasts that were injected turned into scar tissue, which caused retinal detachment.

In addition, we have seen indications that patients getting IV infusions of stem cells might be at some risk for heart attacks. Perhaps via clot formation. For example, read this piece: Cellular Performance Institute death.

One of the challenges is that it can be difficult to figure out if heart attacks or other outcomes were linked to the actual stem cell procedures or just incidental. Many patients getting stem cells may already be at higher risks for these issues. In any particular case, one can ask: was the cell infusion linked to the death? Im not sure we could ever know. Such outcomes should be carefully tracked and analyzed. One challenge is that adverse events at hundreds of unproven clinics may never be reported or otherwise come to light.

Specific routes of administration may pose unique risks as well. For instance, intranasal stem cells are getting popular with some unproven clinics and could lead to cells or other material ending up in the brain. Intranasal delivery of stem cells could have real promise such as for treating brain conditions, but you need rigorous clinical data to back that up. You need to work with the FDA and send them data. Clinics without such data are already selling the procedure.

Other products in the regenerative sphere that are not stem cells may be risky as well for various reasons. For instance, an exosome product harmed quite a few people in Nebraska. Some problems may relate to product contamination. Here again, exosomes may have promise for some conditions but should not be sold already as therapies at this time.

Finally, stem cells and other cell therapies also pose unknown risks because of their newness and power.

We also just dont have long-term follow-up data to have a clear sense of all major risks after people go to clinics.

In general, so much depends on collecting good data before trying to make money form vulnerable patients.

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Stem cell therapy side effects & risks at clinics - The Niche

IPS Cell Therapy Comments Off on Stem cell therapy side effects & risks at clinics – The Niche | March 11th, 2025

Whether through injury or simple wear and tear, the skins integrity and function can be easily compromised. Although this impacts billions of people worldwide, little is known about how to prevent skin degeneration.

The Harvard Stem Cell Institute (HSCI) Skin Program is committed to understanding why skin sometimes fails to heal or forms scars, as well as why skin inevitably becomes thin, fragile, and wrinkled with age. The Skin Programs ultimate goal is to identify new therapies for skin regeneration and rejuvenation.

Wound healing is a major problem for many older individuals. Furthermore, chronic, non-healing skin ulcers are a major source of health care costs and patient morbidity and mortality.

Human skin repairs itself slowly, via the formation of contractile scars which may cause dysfunction. In contrast, the axolotl salamander can readily regrow a severed limb, the spiny mouse has densely haired skin that heals with remarkable speed, and the skin of the growing human embryo can regenerate after trauma without the need for any scar formation. By studying these examples, scientists are finding clues for how to enhance skin healing through a more regenerative response.

During normal wound healing, scars form from dermal cells that align in parallel. But when this alignment is disrupted by a biodegradable scaffold that directs cells to grow in a random orientation, the cells follow the diverse differentiation program necessary for true regeneration.

HSCI scientists have also identified biomarkers for the key cells involved in skin regeneration, and are developing therapeutic strategies for their enrichment and activation. Ongoing clinical trials are using skin stem cells to treat chronic, non-healing ulcers, and early results are promising.

Additional approaches include 3D bioprinting, where skin stem cells are layered into a complex structure that mimics skin and could be potentially used for transplantation.

Skin aging can be thought of as a form of wounding, in which stem cells no longer maintain normal skin thickness, strength, function, and hair density. Understanding how to harness stem cells for scarless wound healing will also provide key insights into regenerating aged skin, a process termed rejuvenation. Multidisciplinary collaborators in the HSCI Skin Program are investigating the biological basis for how the skin ages over time and when exposed to ultraviolet radiation.

In addition to aging, skin stem cells also may mistake normal regions of the skin as wounds, then erroneously attempt to fill them. HSCI investigators are exploring whether this may be one of the underpinnings of psoriasis, a common and devastating disorder.

These areas of investigation are just the beginning. Skin stem cell biology has the potential to provide key insights into the mechanisms of regeneration for other organs in the body.

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Skin Regeneration and Rejuvenation | Harvard Stem Cell Institute (HSCI)

Skin Stem Cells Comments Off on Skin Regeneration and Rejuvenation | Harvard Stem Cell Institute (HSCI) | March 1st, 2025

1. Introduction

Stem cells are unspecialized cells and are the essential building blocks of all organisms. They can differentiate into any specialized cell within an organism [1]. In this capacity, stem cells possess the ability to self-renewal, in addition to differentiating into all cells within tissues and ultimately organ systems [2, 3, 4]. Stem cells exist from conception and remain functional through adulthood, with many regulatory factors responsible for their specialization. As stem cells mature, differentiation becomes more limited which is referred to as commitment to a specific lineage. This means a unipotent stem cell is restricted in differentiation compared to a pluripotential stem cell (PSC) that can produce a variety of lineage specific cells. Thus, PSCs are more restricted when compared to a totipotent stem cell (TSC) [5, 6].

TSCs are capable of cell division with the ability to differentiate into mature cells comprising all the physiological systems associated with an intact and complete organism [6]. TSCs have unlimited potential to fully differentiate. This property allows TSCs to form both embryonic and extra-embryonic structures such as the placenta and the tissues associated with pregnancy [7, 8]. An example of a TSC is the zygote that forms after a sperm fertilizes an egg. TSCs will form a blastocyst which develops the inner cell mass (ICM). The ICM contains a unique population of stem cells known as embryonic stem cells (ESCs). ESCs are capable of remaining pluripotent in vitro [9, 10]. ESCs form the three germ layers associated with developmental biology, i.e., ectoderm, mesoderm, and endoderm [10], thus providing the core foundation of an organism through each germ layer by providing all the anatomical and physiological systems of the organism [11].

Pluripotential stem cells (PSCs) form structures associated with only the germ layers [11]. Another example of stem cells possessing pluripotency was achieved following the reprogramming capability to produce induced pluripotent stem cells (iPSCs) [12]. iPSC pluripotency is a continuum, starting from totipotent cells to cells possessing less potency as in multi-, oligo- or unipotent cells. The independence of iPSCs allows for using improved methods that are more promising for therapeutic stem cell use now and for future applications as defined in regenerative medicine [13].

Within their respective lineages, multipotent stem cells can generate more specialized cells. It differentiates blood cell development to form a variety of diverse cells such as erythrocytes, leukocytes, and thrombocytes [14]. A myeloid stem cell is an example where a stem cell may differentiate into different types of leukocytes, e.g., white blood cells such as granulocytes or monocytes, but never erythrocytes or platelets [15].

As mentioned above, during embryogenesis, stem cells form aggregates referred to as germ layers [16]. Once hESCs differentiate into a specific germ layer, they become multipotent stem cells and can only differentiate according to their respective layer. Pluripotent stem cells are present throughout the life of any organism existing as undifferentiated cells [17]. Regulatory signals influence stem cell specialization to create specific tissues that are produced via physical contact between cells through the microenvironment/stroma or as stimulators in the form of cytokines, interleukins, and/or tissue factors secreted by surrounding tissues. These factors from internal sources are controlled via the presence of the genome, i.e., genes, thus DNA acting through transcription translation reactions [11]. Stem cells provide a mechanism designed to function as the bodys internal repair system. For as long as an organism remains functional, its stem cells will continue to provide differentiation pathways to replace more mature cell lineages. This is the repair and replenishment aspect of stem cell vitality [11, 18].

The growth and development of an organism depends on the presence of stem cells. Overall, somatic stem cells such as ESCs can be distinguished based upon their characteristic lineage line of development. ESCs can be derived without isolating them from the inner cell mass; however, their growth potential is limited [11]. ESCs can be propagated in vitro using tissue culture conditions indefinitely without restriction if their growth requirements are maintained [19, 20]. ESCs can be propagated in culture with appropriate culture medium containing essential nutrients [19]. Passage of ESCs is an adequate method of sub-culturing stem cells to propagate their numbers over time. Because ESCs are totipotent, they can differentiate into every cell type required in any organ cell system [21]. However, because totipotent stem cells demonstrate immortality, ethical restrictions restrict the procurement of these cells. The origin of these totipotent stem cells is from the ICM of the blastocyst present in embryos. Thus, the procedure to obtain them destroys the viability of that embryo from further development. However, most ESCs are derived from fertilized eggs in an in vitro clinic rather than from eggs harvested from pregnant women [22].

Among the many stem cell types that exist are as follows:

Hematopoietic stem cells have the potential to differentiate into many types of blood cells, e.g., erythrocytes, leukocytes, and thrombocytes.

Mesenchymal stem cells are found in multiple types of tissues. They can differentiate into multiple lineages such as bone, adipose, vascular, and cartilage tissue. They can be harvested from sources including but not limited to the umbilical cord, bone marrow, and endometrial polyps [23].

Neural stem cells develop into glial or neuronal cells such as nerve cells, oligodendrocytes, and astrocytes. These cells have been used in treatments regarding Parkinsons disease through transplants [24].

Skin stem cells (SSCs) consist of several types that are separated into their own niches including hair follicle stem cells, melanocyte stem cells, and dermal stem cells. SSCs have greater potential to be used for stem cell therapies and treatments since these cells can differentiate into more cell lineages [25].

Human ESCs are involved in whole-body development and can eventually become pluripotent, multipotent, and unipotent stem cells. Compared to adult somatic stem cells, they also have a quicker proliferation time and greater range of differentiation causing them to be more ideal and preferred in therapies [26].

Stem cells can also be taken from the placenta. Placental fetal mesenchymal stem cells can differentiate into a wide variety of cells and are abundant, not requiring invasive procedures to procure. They are not surrounded with ethical issues that ESCs have since the placenta is usually considered medical waste after birth, making it favorable for use as treatment. They can produce ectodermal, endodermal, and mesodermal lineages in vitro and contain the same cell markers as ESCs, making them very similar. Placental stem cells are pluripotent and have low immunogenicity which allows them to be ideal for therapies and treatments [27].

Differentiation was thought to be restricted and non-reversible. However, after several major experiments through cloning, even differentiated cells can be reprogrammed or induced to be pluripotent. Two major cloning-related discoveries were made in 1962 and 1987. The first was done by John Gurdon who cloned frogs through the process of somatic nuclear cell transfer (SNCT) into an enucleated frog egg [28]. This showed that the nucleus of a specialized somatic cell could be reverted and develop cells that could eventually produce an entirely new organism [29]. The specialized somatic cell became pluripotent which, before this experiment, was thought to be impossible [30, 31]. This technique was famously used successfully in the cloning of Dolly, the sheep [28]. The 1987 experiment focused on gene expression. The forced expression of one gene, known as myogenic differentiation 1 (Myod1), could cause fibroblasts to turn into myoblasts [32]. This was another example of transforming cells, but this was done through programming the cell in the DNA.

These discoveries provided the turning point in stem cell research by advancing the therapeutic application of stem cells when a Japanese team of scientists showed adult multipotent stem cells could be reverted into a pluripotent state. These cells functioned like ESCs but did not need to be acquired from embryos. This discovery created a process to avoid endangering the life of a fetus to obtain ESCs. The determining factor in the process using murine fibroblasts was incorporating a retrovirus-mediated transduction system containing four transcription factors found in ESCs known as Oct-3/4, Sox2, KLF4, and c-Myc [17]. These factors induced the fibroblasts to become pluripotent. The newly formed reprogrammed stem cells were named induced pluripotent stem cells (iPSCs). A later study succeeded using human cells [33]. This technological breakthrough created a new line of research in stem cell biology that coincided with the generation of iPSC cell lines. Importantly, as mentioned, iPSCs can be made biocompatible with any patient, thus dramatically improving the therapeutic potential of this newly created cellular therapy [13]. ESCs are still the only naturally occurring pluripotent cells, but from these experiments, terminally differentiated cells can be induced into pluripotency to become iPSCs. Still, reprogramming cells comes with risks to cellular development due to histone alteration. However, an experiment was done by sequencing DNA from murine iPSCs and confirmed that although mutations were introduced, reprogramming cells could create iPSCs that were not seriously genetically affected or produce ill-functioning cells [11, 34].

As these cells are manufactured, controlling the quality of iPSC lines is necessary for use as treatments. Ways that they are controlled for their quality are as follows (Table 1) [35]:

Different ways that stem cells can be verified and tested during growth to ensure their quality and viability.

A common source for iPSCs includes fibroblasts. Especially in treatments, taking the patients own fibroblasts for the treatment has shown to be beneficial as the autologous cells do not risk being rejected. However, at first, they were the only source that could be used, and obtaining these cells required a biopsy. Thus, further research was conducted to enhance the techniques efficiency. Other cell types have also been reprogrammed, but fibroblasts are still preferred since their stimulation can be fast and controlled [36, 37].

Stem cells are only potentially useful if they can be differentiated into specific lineages. If not, they can form a teratoma in vivo. However, this condition can be regulated; therefore, if the process can be controlled, it allows clinicians and researchers to improve their therapeutic use when using specific signaling pathways for differentiation. In regenerative medicine, it is important to ensure that these cells will then differentiate in a timely and efficient manner. Directed differentiation exists to push the ESCs to differentiate. As cells develop, they send out signals within their surroundings [38]. Messages from the extracellular environment can also control the differentiation of stem cells which has been shown in in vitro cultures [39]. This can be done easily in in vitro cultures by controlling the conditions in culture. However, replicating such environments in vivo, has been challenging, requiring strict culture conditions [11].

For hESC treatments to be used on patients, the therapies must be culture-free, meaning the stem cells are not contaminated with any feeder or animal cell components [40]. The FDA requires this pertaining to procurement and storage of any type of stem cells contemplated for human use [41]. A difficulty in procuring these treatments is that great amounts of these cells used for treatment must be cultivated in the absence of feeder cells.

Directed differentiation protocols replicate the development of the ICM during embryogenesis. Pluripotent stem cells differentiate into derived progenitors from each of the three germ layers, just as is observed in vivo. Specific molecules act as growth factors to induce stem cells to become specific progenitor cells eventually to develop into a specific cell type. Growth factors function as important regulatory molecules that affect germ layer development in vivo; examples include bone morphogenic proteins (BMP) [42, 43], fibroblast growth factors (FGFs) [44], transcription factors of the Wnt family [45], or transforming growth factors-beta (TGF). How each factor influences germ cell differentiation is unclear and research is ongoing.

The concentration levels and duration of action of a targeted signaling molecule such as a growth factor produces a variety of outcomes. However, the high cost of recombinant molecules currently restricts their routine use in therapy limiting their clinical application. A more promising approach is to focus on using small molecules, thereby activating or deactivating specific signaling pathways [46]. These methods are effective in improving reprogramming efficiency by helping to generate cells that are compatible with the target tissue type. Also, they offer a more cost-effective and non-immunogenic therapy method [47]. Endogenously generated small molecules, e.g., retinoic acid is effective for patterning nervous system development in vivo. It functions effectively in embryonic development where it is used in vitro in culture systems to induce the differentiation of somatic cells [48, 49]. These cells can also induce retinal cell formation when hESCs are used [50]. Through the control of biochemical signals and the environment as important factors can be essential to achieve optimal hESC differentiation when culturing stem cells.

Culture systems have been regulated by multiple agencies around the world including the Food and Drug Administration (FDA) and the European Medicine Agency (EMA). Initially, animal-derived products were utilized, however, that introduced possible animal pathogens. Some stem cell lines derived from embryos and human feeder cell lines have been established which include stem cell-derived cardiac progenitors and mesenchymal stem cells. Xeno-free culture systems also include the development of human foreskin fibroblasts (HFFs) [11, 51, 52, 53].

Stem cells hold immense promise as an important therapeutic option for the future of medicine. Beyond their crucial role in regenerative medicine, stem cell research has demonstrated their intricate processes when involved in growth development. In stem cells, DNA is loosely organized, allowing genes to remain active. Differentiated cells differ in that these cells deactivate certain genes and activate others that are essential to the signals that the cell receives. This process is reversible, demonstrating that pluripotency can be induced through specific gene modifications. Several core transcription factors including Oct3/4, (SRY)-box 2, and Nanog genes have been found to keep these cells pluripotent [17, 54]. Nuclear transcription factors Oct3/4 and Sox2 are crucial for producing iPSCs [54].

Presently, various therapies using stem cells are offered as treatments for conditions like spinal cord injuries, heart failure, retinal and macular degeneration, tendon ruptures, and type 1 diabetes [52, 55, 56, 57, 58]. Stem cell research improves our understanding of stem cell physiology, potentially leading to new treatments for presently untreatable diseases. Many of which are dermatological disorders which were previously thought to have no good solution. This chapter focuses on the application of stem cells treating various dermatological disorders and compliments recent reviews on the same topic [11, 59].

Stem cell therapy has not been actively used as a solution for restoring hair growth, but current results are promising. One study used harvested autologous adipose-derived stromal vascular cells through injected into the scalp of 20 patients with alopecia areata (AA) [60]. At three and six months of follow-up, all patients produced statistically significant hair growth. Adipose-derived stem cell conditioned medium (ADS-CM) contains growth factors essential for hair follicle regrowth such as basic fibroblast growth factor, hepatocyte growth factor, platelet-derived growth factor, vascular endothelial growth factor, and transforming growth factor-beta (TGF-) [61]. Another study isolated human adult stem cells by centrifuging human hair follicles obtained through punch biopsy and injected them into the scalps of 11 androgenetic alopecia (AGA) patients resulting in an increase in hair density and count compared to baseline and placebo [62]. In a larger study with 140 AGA patients, autologous cellular micrografts containing HFSCs were used as a treatment. Within one session, over two-thirds of the patients showed positive results while there was significant increase in their regrowth and thickness [63, 64].

A study randomly assigned 40 patients (20 with AGA and 20 with AA) to receive either autologous bone marrow-derived mononuclear cells or autologous follicular stem cell injections into the scalp, found significant improvement in hair loss with no significant difference between the two preparations [65]. An investigation introduced a novel stem cell method, termed stem cell educator therapy in which patients mononuclear cells are separated from whole blood and allowed to interact with human cord bloodderived multipotent stem cells, thus educating these stem cells after returning them to patients [61]. In nine patients with severe AA, all but one experienced improved hair regrowth of varying degrees. Two patients (one with alopecia totalis and one with patchy AA) experienced complete hair regrowth at 12weeks without relapse after two years. A combination of platelet-rich plasma and stem cell technology also showed promising results [61].

Numerous murine studies have demonstrated the progression of allergies in atopic dermatitis (AD) can be inhibited by using umbilical cord blood mesenchymal stem cells (UCB-MSCs), bone marrow mesenchymal stem cells (BM-MSCs), or adipose-derived mesenchymal stem cells (AD-MSCs) [66, 67, 68, 69]. It is important to consider the type of stem cell used, the number of cells transplanted, the preconditioning of the cell preparation, the therapys relevant targets, and the route and frequency of administration. One example highlighting the complexity of stem cell-based therapy was shown in a study where human UCB-MSCs were pre-treated with mast cell granules [68]. This pre-treatment method enhanced their therapeutic effectiveness, as evidenced by the reduced signs of AD in a NC/Nga mouse model. It was found that hUCB-MSCs primed with mast cell granules were more effective in suppressing the activation of mast cells and B lymphocytes compared to nave MSCs, both in vitro and in vivo [70].

Despite promising results from murine studies in AD, only a few clinical trials have been conducted. In one study, a single subcutaneous administration of hUCB-MSCs was given to 34 adult participants with moderate-to-severe AD [66]. The improvement in AD symptoms was measured using the eczema area and severity index (EASI) score. Treatments for both low and high doses of hUCB-MSCs showed symptom improvement. In the higher dose group, six out of 11 subjects experienced a 50% reduction in EASI score, with no reported side effects. Additionally, typical biomarkers of AD, such as serum IgE levels and the number of eosinophils, decreased after treatment.

A later clinical trial had the injection of clonal mesenchymal stem cells (MSCs) into five patients with atopic dermatitis (AD) who had not responded to conventional treatments [71]. Patients received either one or two cycles of MSC treatment. Effective treatment was evaluated using cytokine biomarkers (CCL-17, CCL-22, IL-13, IL-18, IL-22, and IgE) and EASI scores. Results showed four out of five patients achieved more than a 50% reduction in EASI scores after one treatment cycle. Additionally, significant decreases in IL-13 and IL-22 levels were observed with other biomarkers showing decreasing trends during the studies.

In a more recent phase 1 clinical trial published in 2024, 20 subjects were treated intravenously with human clonal MSCs, given a low dose of cells in Arm 1 and a higher dose in Arm 2. There was an overall improvement for both arms, and the difference in dosage did not make a statistically significant effect. A phase 2 trial proceeded and was randomized, double-blind, and placebo controlled. In this, 72 subjects were tested. The half given the treatment were given the high dosage of hcMSCs originally tested in phase 1. Compared to the placebo group, the treated group had a statistically significant improvement response [72]. These findings suggest MSC administration might help normalize the immune system in AD patients. However, further studies are needed to understand the long-term mechanisms and effects of MSC treatment in this context.

Dermatomyositis remains a mystery with its exact etiology still unknown. Research using stem cells to treat the disease is limited with few studies and case reports available. One report detailed successful autologous stem cell transplants for two patients with juvenile dermatomyositis who had not responded to initial treatments [73]. In the first patient, the procedure involved transferring CD3/CD19-depleted mobilized peripheral blood mononuclear cells (PBMCs), which included 7.5106/kg CD34+ stem cells and 2.9104/kgT cells. Following a 26-month follow-up period, significant improvements were observed. The Childhood Myositis Assessment Scale (CMAS) score increased from 6 to 51and the manual muscle testing (MMT) score rose from 61 to 150. These results demonstrated a substantial improvement in symptoms with the patient regaining the ability to walk and showing significant reductions in inflammatory reactions after the autologous stem cell transplant.

In the second patient, a similar response was observed. The patient was treated with CD3/CD19-depleted autologous PBMC graft (7.51106/kg CD34+; 1.6104/kg CD3+). After three months of treatment, the patient had less muscle pain and contractures, and she began also regained the ability to walk [73].

An uncontrolled study in which 10 patients received allogenic mesenchymal stem cell therapy was reported where one or two MSC infusions were given to patients depending on whether they had disease recurrence within a short time after initial treatment. Out of the 10 patients, eight showed significant clinical improvement, with their symptoms improving after MSC therapy [74]. However, further research is required to evaluate the long-term effects of MSC treatment in patients with dermatomyositis.

Epidermolysis bullosa (EB) is a genetic condition that currently has no treatment, but stem cell therapy is one cell-based therapy under investigation that may be able to correct the skin and its underlying genetic component. Autologous or allogenic stem cells are options that can be used, with mesenchymal stem cell therapy showing potential; therefore, they may be more useful in alleviating some symptoms when tested in additional studies.

One study followed two patients with severe generalized recessive dystrophic epidermolysis bullosa (EB) treated with intradermal administration of allogenic mesenchymal stem cells from bone marrow showed complete healing of ulcers around the treated site by 12weeks [75]. Type VII collagen was detected along the basement membrane zone and the dermal-epidermal junction was continuous in the treated site 1week after treatment. Unfortunately, the clinical effect lasted for only 4months in both patients.

In the case of junctional EB treated with primary cultured keratinocytes, it showed normal morphology and the absence of spontaneous and induced blisters or erosions at 21months of follow-up [76]. Studies using BMSCs to treat recessive dystrophic EB have also shown promise [77, 78]. One study investigated 10 recessive dystrophic EB children treated with intravenous allogeneic bone marrow-derived mesenchymal stem cells and found that the procedure was well tolerated with minimal side effects over the nine-month period [79]. However, skin biopsies performed at the two-month time point showed no increase in type VII collagen and no new anchoring fibrils. While the initial clinical improvement was favorable, it was not maintained over time due to insufficient production of durable proteins like collagen and laminins. The current evidence for stem cell therapy in treating EB is limited because few patients have been treated. This underscores the need for additional research to assess the therapys effectiveness and the balance of its risks and benefits [80].

Despite significant progress in understanding psoriasis pathogenesis in recent years, it remains unclear what is the exact etiology. Current research suggests that dysfunction in certain types of stem cells might be a primary cause of the inflammatory response dysregulation in psoriasis [81]. This hypothesis came after observing long-term remission in psoriasis patients who underwent hematopoietic stem cell therapy [82, 83]. Conversely, there have been reports of acquired psoriasis in patients who received bone marrow transplants from donors with psoriasis, indicating a significant role of hematopoietic stem cells in disease pathogenesis [84, 85]. MSCs have also shown success in treatment likely due to their engraftment, paracrine, or immunomodulatory effects [86]. However, the availability of cost-effective and safe alternatives limits the use of stem cell transplantation as a practical option for treating psoriasis.

Scleromyxedema is a chronic fibro-mucinous disorder that can result in respiratory complications. A study conducted on five patients who underwent high-dose chemotherapy followed by stem cell rescue led to durable remission in most cases, although it did not cure the disease [87]. Another study showed scleromyxedema was successfully treated with chemotherapy and autologous stem cell transplantation [88]. The patient achieved complete recovery within six months and remained in remission for 3years post-transplantation. In a 2022 report, a male patient underwent an autologous hematopoietic stem cell (HSC) transplant after previous therapies failed to improve his symptoms. Improvements were seen in the patients skin, but the renal and pulmonary complications required the use of steroids and plasmapheresis. Unfortunately, the patient contracted SARS-CoV-2 virus and died [89]. More studies still need to be done to determine if stem cell therapy might be useful alone or combined with other therapies to treat scleromyxedema.

Systemic sclerosis (SSc) is an autoimmune disease characterized by excess collagen in the internal organs and skin, causing ulcers and organ damage. HSC therapy and MSC therapy have been tested and found to improve pain, blood flow, lung function, among other symptoms of the disease [90]. Autologous hematopoietic stem cell therapy is preferred over allogeneic therapy due to its lower treatment-related mortality and absence of graft-vs.-host disease [91].

Stem cell therapy has been extensively studied in three randomized controlled trials: the American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST, phase 2, 19 patients), the Autologous Stem Cell Transplantation International Scleroderma Trial (ASTIS, phase 3, 156 patients), and the Scleroderma Cyclophosphamide or Transplantation study (SCOT, phase 3, 75 patients), with several pilot and case studies [92, 93, 94]. These studies have demonstrated autologous hematopoietic stem cell therapy is an effective and safe treatment for systemic sclerosis. However, patients with severe major organ involvement (pulmonary, cardiac, or renal) or serious comorbidities were excluded from all three trials due to contraindications [59].

MSC therapy has the ability to suppress innate and adaptive immunity and can differentiate into a wide variety of tissues, making it seem like an ideal choice for SSc [95]. However, if donors are not carefully chosen, there is the chance that collagen production can be increased, thus this therapy can worsen symptoms [96]. This research suggests that autologous MSCs from patients that have advanced stage SSc should not be used for treatment. On the other hand, allogenic MSC therapy has lived up closer to the promises of stem cell therapy. Allogenic MSCs were administered intravenously in a female patient, where her skin condition improved, reducing the appearance of ulcers and her pain score [95]. In a clinical trial, combining MSC therapy with plasmapheresis was shown to improve lung function and skin thickness shown in improved modified Rodnan Skin Scores. The current research suggests that MSC therapy may be most effective when paired with another therapeutic option, but research still needs to be done to explore this.

Stem cell therapy has been found to be more effective than conventional immunosuppressive drugs and is currently the only disease-modifying strategy that improves long-term survival, prevents organ deterioration, enhances skin and pulmonary function, and improves overall quality of life.

The European Society for Blood and Marrow Transplantation (ESBMT) and the British Society of Blood and Marrow Transplantation (BSBMT) classify autologous hematopoietic stem cell therapy in severe resistant cases as a clinical option, requiring a risk-benefit assessment [97, 98]. Guidelines from the American Society for Blood and Marrow Transplantation (ASBMT) categorize this therapy as standard of care, rare indication for children (indicating it is an option for individual patients after careful risk-benefit evaluation) and developmental for adults [98]. Patients with acute onset rapidly progressive disease refractory to conventional therapy and mild initial organ damage carry a better prognosis after HSC therapy. Patients with long standing conditions, indolent course and/or irreversible organ damage are contraindications to this therapy [99]. Thus, the challenge is to identify patients who are likely to be benefitted with HSC therapy.

HSC therapy has been tested in patients with refractory systemic lupus erythematosus (SLE). Many observational studies and clinical trials have been aimed at assessing the effectiveness and safety of this transplant approach [100, 101, 102]. In a long-term follow-up of a female patient who underwent allogenic BM-HSC treatment, her systemic lupus erythematosus disease activity index (SLEDAI) score was found to improve, pain improved, and engraftment remained functional [103]. Collectively, these reports show HSCs to be beneficial for patients with a shorter duration of refractory disease suggesting that earlier intervention might lead to better outcomes [104].

The therapeutic potential of MSCs has been investigated for various autoimmune diseases including SLE [105]. In a recent study, six refractory SLE patients were treated with an intravenous infusion of MSCs. Five of the patients reached the threshold for improvement, achieving an SLE Responder Index (SRI) of 4 [106]. In a separate long-term follow-up study done in 2021, 81 patients were treated with allogenic BM-MSC and/or UC-MSCs. After 5years, 37 patients had achieved clinical remission. MSC therapy has been shown to improve patient survival and reduce the severity of the disease as it has been shown to be safe and effective in treatments [107]. MSCs have been shown to alleviate SLE severity, improve renal function, decrease autoantibody production, upregulate peripheral T-cells, and restore balance between Th1- and Th2-related cytokines [108]. These collective immunomodulatory and regenerative properties position MSCs as a promising treatment for SLE.

Steroid topical treatment is the first line of therapy for vitiligo, but when it proves ineffective, surgical options may be viewed next [109, 110]. Cellular grafts using autologous non-cultured outer root sheath hair follicle cell suspension (NCORSHFS) have been tested as a method to treat vitiligo [111]. This method utilizes the regenerative capacity of hair follicle melanocytes, as they can repigment areas where vitiligo has caused depigmentation by allowing melanocyte precursors to proliferate into the areas that lack melanocytes, making them preferable over epidermal melanocytes for cell-based vitiligo treatments. One study reported NCORSHFS achieved an average repigmentation rate of 65.7%, with more than 75% repigmentation observed in nine out of 14 patients [112]. Another study investigated factors affecting therapeutic outcomes in 30 patients with 60 target lesions treated with NCORSHFS [111]. They found that 35% of the lesions achieved repigmentation greater than 75%. The study showed patients who achieved optimal repigmentation had significantly higher numbers of transplanted melanocytes and hair follicle stem cells. Also, the absence of dermal inflammation was a significant predictor of successful repigmentation. These results emphasize the importance of specific cellular components, and a favorable dermal environment is necessary for the effective treatment of vitiligo with NCORSHFS.

Another promising stem cell treatment for vitiligo is multilineage-differentiating stress-enduring (MUSE) cells [113]. In three-dimensional skin culture models, ex vivo studies have identified factors that encourage MUSE cells to differentiate into melanocytes. The melanocytes are integrated into the epidermis, promoting melanogenesis. However, the impact of MUSE cells in vivo remains to be determined [114].

Chronic or non-healing skin wounds present an ongoing challenge in advanced wound care. Current wound healing treatments remain insufficient. Stem cell therapy has emerged as a promising new approach for wound healing using MSCs [115]. MSCs are an attractive cell type for cell-based therapy due to their ease of isolation, vast differentiation potential, and immunomodulatory effects during transplantation. MSCs are known to play a key role in the wound healing process making them an obvious candidate for clinical use. When introduced into the wound bed, MSCs have been shown to promote fibroblast migration, stimulate extracellular matrix (ECM) deposition, facilitate wound closure, initiate re-epithelialization, enhance angiogenesis, and mitigate inflammation in preclinical animal models. MSC efficacy and safety use for the treatment of chronic wounds was further confirmed by several clinical studies involving human subjects which yielded similar positive results with no adverse side effects [116]. However, while MSCs appear to be a promising resource for chronic wound care, additional studies are needed to determine optimal cell source and route of delivery before this treatment can be recommended for clinical use.

MSCs for the treatment of chronic wounds has proven to be feasible, effective, and safe, reported through preclinical and clinical trials [117]. MSCs stimulate the healing process in chronic wounds through several biological and molecular mechanisms. One of the primary roles of MSCs is to promote the directional migration of fibroblast cells to the injury site where they can localize in the wound bed [115, 118]. Once localized fibroblasts facilitate wound closure and synthesize the necessary components of the ECM such as collagen. MSCs can also downregulate MMP-1, a type of collagenase primarily responsible for ECM degradation. MSCs function to preserve ECM and maintain dermal structure. MSC-treated wounds have increased elastin levels which provides recovering tissue with resiliency that is not typically seen in normal wound healing [116]. MSCs play a role in the re-epithelialization process by activating the proliferation, differentiation, and migration of keratinocytes that support the formation of a multi-layered and well-differentiated epidermis [117, 119].

MSCs are believed to stimulate the development of new hair follicles and sweat glands, which suggests these stem cells are capable of not only accelerating wound healing but also improving the quality of wound healing. MSCs use for chronic wounds supports angiogenesis by upregulating VEGF and Ang-1 increasing microvessels throughout the wound bed [120]. This allows the nutrient and oxygen transport to developing cells enhancing their longevity. Also, MSCs help to modulate the wound environment and in turn support proper healing by mitigating inflammation at the site of injury. Importantly, MSCs decrease infiltration of inflammatory cells and pro-inflammatory cytokines and initiate the polarization of M1 macrophages to anti-inflammatory M2 macrophages. MSCs also downregulate ICAM1, a protein involved in inflammation, and upregulate superoxide dismutase, an enzyme which breaks down harmful superoxide radicals [118, 121]. By supporting wound healing MSCs by optimizing the healing environment can produce efficient wound closure.

Several clinical trials in human subjects have generated positive results when MSCs were applied to chronic or non-healing wounds [122]. No adverse side effects have been observed which confirms the safety and feasibility of this cellular therapy for human application. However, further research is needed to determine the best cell source and route of delivery before this procedure can be recommended for human use clinically.

MSCs can be isolated from various tissue types including bone marrow, adipose tissue, cord blood, and placenta. MSCs demonstrate unique properties. Several comparative studies have reported MSCs as the most promise for cell therapy due to their abundance and ease of isolation as well as their regenerative and immunomodulatory properties [123]. How these MSCs are delivered into the wound is the critical question. MSCs can be delivered locally to the wound bed via injection, topical application, or incorporation into a 3D scaffold to avoid issues related to low engraftment efficiency observed following IV injection [124, 125]. Investigating local delivery methods, MSCs seeded into a biomaterial scaffold appears to hold promise as it allows for the localization of the cells into the wound bed and provides donor cells with protection and structure [126, 127]. Following additional research, the application of MSCs for chronic or non-healing wounds could provide a major development in advanced wound care.

Epidermal stem cells have potential to regenerate the epidermis and differentiate under appropriate stimuli into various skin cell types and tissues [128]. This property can be used to initiate and accelerate healing of chronic non-healing wounds. MSCs promote wound healing by decreasing inflammation, promoting angiogenesis, and decreasing scarring [129]. One study successfully applied human MSCs to non-healing and acute wounds using a specialized fibrin spray system [130]. Another study demonstrated the efficacy of stem cell therapy in diabetic foot ulcers [131].

Read more:
Stem Cell Use to Treat Dermatological Disorders - IntechOpen

Skin Stem Cells Comments Off on Stem Cell Use to Treat Dermatological Disorders – IntechOpen | March 1st, 2025

Scientists have managed to reprogram human skin cells directly into cells that look and act like embryonic stem (ES) cells. The technique makes it possible to generate patient-specific stem cells to study or treat disease without using embryos or oocytes--and therefore could bypass the ethical debates that have plagued the field.

Originally posted here:
Researchers Turn Skin Cells Into Stem Cells | Science | AAAS

Skin Stem Cells Comments Off on Researchers Turn Skin Cells Into Stem Cells | Science | AAAS | March 1st, 2025

Covering an average surface area of 1.85 m2, and accounting for ~15% of total body weight, the skin is considered the largest organ in the human body. Its primary function is that of a physical barrier against microbial pathogens, toxic agents, UV light, and mechanical injury [1]. However, this function can also extend into other vital functions, such as thermoregulation, protection against dehydration, and the excretion of waste metabolites [2]. Moreover, the skin also represents a major metabolic site, yielding a broad range of biomolecules, e.g., vitamin D [3].The skin is composed of two main layers, i.e., the epidermis and the dermis. Previously, another layer had been described within the skin, i.e., hypodermis [4]; however, there is an ongoing controversy in this regard and the hypodermis is now considered as part of the dermis. The skin contains accessories, such as hair, nails, and sweat, and sebaceous glands [5]. In addition, the skin is also populated by nerve receptors that can be triggered by external stimuli (e.g., touch, heat, pain, and pressure) [6]. The skin layers have different thickness according to their anatomical location; for example, the epidermis can be very thin in the eyelids (0.1 mm) whereas it can be thicker in the palms and soles of the feet (1.5 mm). In contrast, the dermis can be ~3040 times thicker in the dorsal area than the corresponding epidermal layer [2].The epidermis can be further sub-divided into strata with a unique cell composition, i.e., keratinocytes, dendritic cells, melanocytes, Merkels cells, and Langerhans cells. These epidermal layers are known as stratum germinativum, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The first of these strata, also known as the basal cell layer, conforms the inner-most part of the epidermis [2,7]. It is in this layer that different populations of stem cells (SCs) are located, and which, through extensive proliferation and differentiation, provide the great regeneration capacity of the skin and enable the generation of auxiliary structures, e.g., nails and sweat glands [8]. It must be mentioned that the basal cell layer is not the only stem cell niche within the skin as these cells can also be found within the hair follicle (HF), interfollicular epidermis (IFE), and sebaceous glands [8], all of which are contained within the basal layer itself. The stem cells within the skin are usually named after the niche in which they reside in, i.e., hair follicle stem cells (HFSCs), melanocyte stem cells (MeSCs), interfollicular epidermis stem cells (IFESCs), and dermal stem cells (DSCs). Regardless of their niche, these cells are collectively known as skin stem cells (SSCs) (Figure 1).The main task of these SSCs is to replace, restore, and regenerate the epidermal cells that may have been lost, damaged, or have become pathologically dysfunctional [9,10]. For such end, a carefully orchestrated cell division, both symmetrical and asymmetrical, is required to both maintain the stem cell pool and produce lineage-committed cell precursors [11]. Initially, SSCs were thought to be age-resistant, mostly because their number does not seem to dwindle through time [12,13]. However, despite their longevity, SSCs eventually become unstable or dysfunctional and display a lower differentiation and self-renewal capacity [14].As previously mentioned, SSCs are found in diverse niches within the skin, of which the hair follicle has been the most studied. The distinct anatomical zones of the HF can house different stem cell types, such as HFSCs and MSCs [15,16]. The bulge region of the HF contains different stem cell populations; however, the exact identity of these cells is still unclear. Regardless, the presence of both proliferative (CD34+/LGR5+) and quiescent (CD34+/LGR5) stem cells has been described in previous research [16,17].Overall, the diverse subpopulations of SSCs have specific characteristics that set them apart from one another. For instance, HFSCs are mostly quiescent until triggered by several factors secreted by their progeny and by adjacent dermal cells [18]. Regarding the former, their isolation has been so far complicated by the lack of specific markers to identify them [19]. In addition to the hair follicle bulge, SSCs can also populate the sebaceous glands; however, these stem cells are thought to be unipotent and dedicated exclusively to the renewal of the sebocytes pool [16,20]. Other proposed niches are found within the compartments of the dermal papilla (DP) and the dermal sheath (DS) [9,16] and, unlike the stem cells located in the sebaceous gland, those located in both the DP and DS display a greater differentiation capacity, even being able to differentiate into cells of hematopoietic lineages [9], and have also been involved in the maintenance and repair of the dermal tissue. Melanocyte stem cells (MeSCs) are also located in the bulge and hair germ of the HF. Interestingly, their proliferation and differentiation seem to be closely tied to that of HFSCs [21]. Therefore, the concurrent activation of both MeSCs and HFSCs by the signals originating from the latter is hardly surprising. Due to their embryonic origin (i.e., neural crest), MeSCs possess high proliferative and multipotent capacity, which makes them interesting for regenerative medicine [22] and stem cell-based therapies [15,23]. In this regard, dermal stem cells (DSCs) are also considered as an accessible and abundant source for stem cell-based therapies [24] as they display great plasticity and the potential to differentiate into cells of ectodermal, mesenchymal, and endodermal lineages [24,25]. Consistently, the niche of these cells has been localized to the DP and DS [26]. IFESCs, on the other hand, are difficult to isolate and identify due to their unclear location within the basal layer. Therefore, their study has been mostly conducted through indirect means, such as screening with cell surface markers [27,28] or lineage analysis and tissue regeneration assays [29].Before delving further and in trying to bring greater clarity to the previous paragraph, let us recapitulate the existing models for skin stem cells that are currently being considered. The earliest model describing the hierarchy of stem cells in the interfollicular epidermis suggests the columnar arrangement of keratinocytes stacked in what is known as epidermal proliferative units (EPU) [30]. According to this model, stem cell clones are similar in size and their number remains rather constant during homeostasis. Relatively few basal cells have stem cell properties and can create transit amplifying (TA) cells, which constitute the majority of basal cells. This model suggests that TA cells go through several proliferation cycles before leaving the basal cell layer and follow their terminal differentiation program [31].Despite the seeming adequacy of this model, a relatively recent study showed that the size of epidermal clones increases over time, which contradicts the previous EPU model. Therefore, a stochastic model was proposed where the basal cells have inherent progenitor characteristics and their differentiation occurs at random. This apparent asymmetry in the cell population results in a scaling behavior in clone size and distribution. Thus, according to this model cell clones become fewer in number and have variable size [32]. Further, this model proposes the existence of a quiescent stem cell population with as few as four to six divisions per year and where progenitor cells present a balanced, although still random, differentiation pattern. However, one in five mitotic cycles would result in progenitor loss, thus suggesting that the population of both stem cells and progenitors might be heterogeneous and with different degree of competence [33].The validity of these theories was later tested in a mathematical simulation in which both the classical hierarchical model and the stochastic model described above would result in stem cell depletion [34]. Therefore, a third model proposed the existence of both a quiescent stem cell population and a committed progenitor population with stochastic differentiation fate [35]. Interestingly, this model could also explain the diminished healing capacity observed in the later stages of life, as the number of stem cells would decline with age. However, it must be kept in mind that all of these models are based in murine models and are not fully applicable in humans. Thereby, further research in this regard is still needed. Due to the extensive nature of this subject in particular, we suggest an excellent review by Dr. Helena Zomer et al. providing greater detail and context [36].

Due to the extensive and complex nature of the subject, the present review conveys a broad overview on SSCs, wound healing and the signaling pathways involved therein, as well as some of the current strategies in stem-cell based treatment strategies for wound healing.

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A Beginners Introduction to Skin Stem Cells and Wound Healing - MDPI

Skin Stem Cells Comments Off on A Beginners Introduction to Skin Stem Cells and Wound Healing – MDPI | March 1st, 2025

Skincare can be so confusing these days. With so many emerging ingredients on the market, it's hard to know which ones are right for you to prevent premature aging, repair damage, and keep your skin clear. Lately, we've seen ingredients like growth factors and exosomes have a moment in the spotlight, but there's another potent skin-renewal helper that we often forget about: stem cells.

According to board-certified dermatologist, stem cell scientist, and cosmetic surgeon Nathan Newman, MD, human stem cells aren't always ideal for use in skincare, because they may carry undesirable pathogens and genes, but plant stem cells don't have this issue and communicate almost identically to human ones.

Newman thinks that stem cells trump all the other options out thereand for good reason. I chatted with him about the difference between stem cells, exosomes, and growth factors to get the full picture. Keep reading for everything he had to share.

Newman broke down the difference between the industry's most popular youth-enhancing ingredients right now.

Exosomes: Exosomes are small vesicles that play a role in intercellular communication and tissue regeneration. They can be derived from stem cells, plants, or human cells. "They are usually processed and not used as they are produced by the cells," says Newman. "The products are unstable and need to be processed and preserved. They are not consistent from batch to batch, so each time it is manufactured, it will have a different set of signals."

Growth factors: Similar to exosomes, growth factors are proteins that play a key role in regulation cell growth and survival. They're already produced by various cells in the body, but many companies make synthetic versions to put into skincare formulas. These proteins signal molecules to promote cell proliferation, tissue repair, and the formation of new blood vessels. According to Newman, though, their effects are short-lived and do not always regenerate tissue. Basically, you can think of exosomes as a vehicle to deliver the message and growth factors as the actual message.

Stem cell factors: Plant stem cells, on the other hand, are the means by which cells communicate and impart their actions on other cells in your body. "The entirety of this cellular language is referred to as secretomes," explains Newman. "Some of these factors are released directly into the space in between cells and others need to be packaged, as they will be degraded outside the cell, and delivered from one cell to another cell. This cellular language is a dialogue between cells, and it sets off a domino effect that can influence thousands of cells in your body by what is referred to as paracrine effect (much like hormones do as part of your endocrine effect)."

Plant stem cells use a similar language to communicate as human cells. Plant-derived stem cell factors are also more accepted for use in skincare and don't carry the risks of communicable diseases as human cells do. Honestly, we don't see too many plant stem cellderived products out there on the market, and that's because the process of reproducing the same set of secretosomes from batch to batch is pretty difficult. But Newman has found a way to create an ideal set that helps the skin regenerate.

"For the first time, there is a patented process that allows the stem cells to be grown in such a way that it will not only produce a consistent set of factors, called Consortia Factors, but the process mentors the cells to produce a specific set of directions to direct the skin or hair to regenerate," he says. "In addition, this process allows the use of any cell, human or plant, to be used to produce Consortia Factors. Unlike exosomes, or isolated factors, Consortia Factors utilize a complex, synergistic network of bioactive molecules that mimic the skins natural healing and regenerative environment. This process allows for consistent and reproducible set of signals that can be studied and used for specific purposes, such as wrinkle correction, hair growth, skin tone [correction], etc."

Take a look below at what I'm using from Newman's stem cellrich line.

STEM Natural Intelligence

RePure Foaming Cleanser

This super-gentle cleanser is so easy on the skin and helps protect the skin's microbiome. It's also infused with stem cells that help preserve hydration and boost your skin's glow with antioxidants.

STEM Natural Intelligence

Stem Reset Moisturizing Facial Spray

This little spray is so handy for a refresh throughout the day, and it's so hydrating. It's another great tool to have in your toolbox for barrier repair because it contains moisturizing polysaccharides and antioxidant-rich gooseberry extract. It gives you a quick boost of serious moisture or is great to use as a setting spray.

STEM Natural Intelligence

Regenerative Serum

This is the crme de la crme of stem cellderived skincare. This serum contains the most stem cell factors out of the entire line and is designed to visibly reduce the appearance of wrinkles, promote even skin tone, and boost elasticity. It also help to support the production of collagen in the skin and floods it with antioxidants that give you a boost of radiance.

STEM Natural Intelligence

Stem Renew Day Cream

Containing a host of skin-perfecting ingredients, this day cream is lightweight and noncomedogenic yet still super hydrating. As with all of Stem's products, this cream contains a host of plant-based stem cells along with vitamin E, Coenzyme Q10, and gluconolactone to mildly exfoliate the skin.

STEM Natural Intelligence

Stem Revitalize Night Cream

The night cream is similar but contains niacinamide and bakuchiol extract to help with dark spots and increase cellular turnover. It also supports your body's anti-inflammatory response and is rich in vitamins A, C, D, E, and K.

The Stem Company

ReGlow Complexion

This was an immediate favorite from the brand after I received a facial with it at Newman's office. Like the name suggests, it gives you an immediate glow. My only complaint is that the bottle is super small and goes fast when you use it as often as I do.

Stem Natural Intelligence

ReLeaf Serum

This one is great for calming acne and inflammation because it contains adaptogens like ashwagandha along with antioxidants. It can also be used almost like a comforting balm to soothe aches and pains.

Lilfox

Flower Goo Botanic Ferment Stem Cell Serum

CLEARSTEM Skincare

Cellrenew Collagen Stem Cell Serum

Angela Caglia

Cell Fort Serum

Originally posted here:
Everything to Know About Stem Cells From a Dermatologist | Who What Wear

Skin Stem Cells Comments Off on Everything to Know About Stem Cells From a Dermatologist | Who What Wear | March 1st, 2025

The world of skincare has seen remarkable advancements over the years, with science-driven ingredients revolutionizing how we support skin renewal and repair. Among the most transformative discoveries are growth factors, stem cells, and exosomes each playing a crucial role in skin rejuvenation. But how do they differ, and how has this technology evolved over time? Lets break it down.

Epidermal Growth Factors (EGFs) are naturally occurring proteins that signal skin cells to regenerate, repair damage, and boost collagen and elastin production. In skincare, EGFs help accelerate healing, improve skin texture, and reduce the appearance of fine lines and wrinkles. They are particularly beneficial for aging and compromised skin, promoting a firmer, more youthful complexion.

Historically, the most potent growth factors came from human or animal sources. However, advancements in biotechnology have enabled the creation of lab-synthesized peptides that mimic the exact chemical structure of natural growth factors. These bioengineered peptides have been proven to accelerate skin renewal, smooth fine lines and wrinkles, enhance skin texture, and combat signs of environmental damage.

Stem cells are undifferentiated cells that have the unique ability to develop into various types of specialized cells. In skincare, stem cell extractstypically from plant or human sourcesare used for their rich composition of growth factors, peptides, and antioxidants that support tissue repair.

NeoGenesis, a pioneer in biotech-driven skincare, developed patented SRM technology that enables the harvesting of an array of molecules from multiple adult stem cell types and packages them in a highly bioavailable exosome delivery system. These powerful molecules include growth factors, cytokines, and other signaling proteins that are crucial for the bodys natural healing process. Their regenerative skincare products provide nutrients that mimic and enhance your bodys own natural stem cell function.

While growth factors are signaling proteins, stem cells act as a source of these growth factorsdelivering a broader spectrum of regenerative compounds that can enhance the skins natural repair mechanisms. Unlike single-function growth factors, stem cell released media works holistically to enhance skin resilience, making them ideal for sensitive, damaged, or aging skin. They support wound healing, improve hydration, and strengthen the skin barrier.

Plant-based stem cells provide an excellent source of antioxidants and anti-inflammatory benefits to keep skin protected from oxidative stress to promote renewal. However, they cannot communicate directly with live human stem cells to encourage regeneration.

Exosomes are tiny extracellular vesicles that act as advanced messengers, carrying a concentrated blend of antioxidants, nucleic acids, peptides, and phosphoproteins directly to cells. They transmit messages to a target cell and train that cell to act in a certain way. With this enhanced cell communication, in the skin, exosomes can accelerate repair and optimize collagen production for a more youthful, radiant appearance. Exosomes offer a more stable and potent alternative to traditional growth factors or stem cells, making them one of the most cutting-edge innovations in regenerative skincare.

( plated ) Skin Science is the first and only company to harness the power of platelet-derived exosomes in skincare and is a standout in biotech-driven skincare. Through years of research, they developed their patented Renewosome technology to deliver the power of platelet-derived exosomes in a shelf-stable serum formulated to regenerate the appearance of the skin. Their gentle extraction method preserves the structure, purity, and potency of the exosomes, ensuring stability for 12 months without refrigeration. ( plated ) Skin Sciences revolutionary technology is clinically proven to deliver targeted peptides and powerful antioxidants to support the production of collagen and elastin and improve the appearance of redness, brown spots, dullness, and wrinkles.

Platelets are the most prolific generators of exosomes.

As a first responder to wound sites, platelet-derived exosomes go directly to the area of damage and play a pivotal role in the skins natural regeneration process.

Exosomes deliver precise, self-regulating signals and naturally deactivate once their job is done, eliminating concerns of overproliferation.

Platelets act as the direct messengers of renewing cues rather than functioning as intermediaries, as with other regenerative cells or exosomes.

As compared to stem cell exosomes, it is easier to extract pure, regenerative cells and to control variables for consistency over time.

Exosomes can target multiple skin concerns simultaneously (e.g., aging, inflammation, and pigmentation).

Their ability to provide targeted cell-to-cell communication makes them the most advanced option for promoting long-term skin health.

Late 1990s Growth factors were introduced in topical skincare, derived from human and plant sources.

Mid-late 2000s Stem cells started appearing in skincare products as the potential for skin regeneration was realized and their role in cellular communication and repair was better understood.

2010 to Present Exosomes have emerged as the next generation of regenerative skincare, offering superior results in cellular repair and collagen synthesis.

( plated ) Skin Science Intense Serum: This revolutionary, advanced regenerative treatment utilizes a proprietary blend of platelet-derived exosomes to deliver next-level skin rejuvenation. It is clinically proven to enhance skin renewal and healing by delivering targeted antioxidants and peptides to improve tone, texture, firmness, elasticity, and overall skin health.

NeoGenesis Recovery Serum: This breakthrough healing serum utilizes patented SRM technology to restore skin to a healthy and radiant state, effectively correcting the most damaged skin. It is rich in stem cell-released molecules containing growth factors, antioxidants, proteins, and peptides to promote healing and improve the signs of aging while reducing redness and inflammation.

Rhonda Allison Radiant Renewal Serum: This serum uses powerful peptide epidermal growth factors (EGF) to directly stimulate the proliferation of skin cells, promoting renewal and encouraging a more youthful, revitalized complexion. It also provides strong antioxidant properties while reducing inflammation and brightening uneven pigmentation.

Le Mieux EGF-DNA: Enriched with proprietary epidermal growth factors (EGF), this concentrated serum repairs skin tissue and stimulates the skins own cell renewal properties to promote firmer, healthier, and more radiant skin.

With advancements in growth factors, stem cells, and exosomes, skincare continues to evolve toward more targeted, effective, and biologically intelligent solutions. While growth factors laid the foundation for regenerative skincare, exosomes are now leading the charge, providing unparalleled benefits in skin repair, hydration, and resilience.

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Lets Talk Skin Rejuvenation: Growth Factors, Stem Cells, and Exosomes

Skin Stem Cells Comments Off on Lets Talk Skin Rejuvenation: Growth Factors, Stem Cells, and Exosomes | March 1st, 2025

Dr. Inta Gribonika in the lab at NIH

Everyones skin may be tougher than they realize. Research led by Dr. Inta Gribonika, a postdoctoral NIH fellow, demonstrates that skin is more than simply a cover from the outside world; it can offer a first line of defense against infection, paving the way for new kinds of therapies.

Gribonika recently completed a four-year stint as a visiting fellow in the Laboratory of Host Immunity and Microbiome at the National Institute of Allergy and Infectious Diseases (NIAID). During her time at NIH, she contributed new knowledge about the skins role in immune response, research that recently was published in Nature.

Her findings show that the skin can act as a lymphoid organ. In other words, a specific immune response can actually be primed in the skin.

Gribonika is a mucosal immunologist. Her doctoral research had focused on how an immune response could be induced in the gastrointestinal tract after vaccination. After reading that the bacteria living naturally on skin is coated in antibodies, she began to wonder how the body could generate antibodieswhich it normally would do against an infectionaround something thats generally harmless.

Up until now, we were thinking that B cellsthe lymphocytes that produce antibodieswere not living in the skin or coming toward the skin tissue at homeostasis, she said. Her experiments show that B cells do exist in healthy skin.

In the lab, Gribonika painted a beneficial bacterium, S.epidermidis, onto the skin of mice. This bacterium is commonly found on human skin, but not on mice.

I showed that, indeed, skin can recognize this new harmless member of microbiota and generate specific humoral immunity against it, she said. This can happen without any help from professional immune organs, such as the spleen or lymph nodes.

The antibody works as a barrier protection, Gribonika said. It works as a health insurance in case this one new member of commensal microbiota that we now acquired decides at some point in the future to become nasty and infect us.

The ability of harmless bacteria on the skin to stimulate an immune response without inflammation opens a world of possibility for topical medications and vaccines. They could be formulated in a cream that anyone could apply to the skin.

This route is so interesting because its noninvasive and you wouldnt need a clinical practitioner to help you apply the medicine, Gribonika said.

In reflecting on her time at NIH, Gribonika emphasized how much she enjoyed getting to know the people in the lab. Each investigator had his or her own project, but they all supported each other. And they came from all over the world, bringing their different cultures and perspectives, which she found especially enriching.

NIH is probably the best place on Earth to do research, she said. There are so many resources, and the community is so welcoming and willing to share.

When she arrived at NIH, Dr. Yasmine Belkaid was her lab chief. She described Belkaid as a visionary who encouraged her trainees to think big. She gave me the space and freedom to ask the questions I wanted to pursue, Gribonika said.

Gribonika studied biology at the University of Latvia in Riga.

Photo: Sergei25/Shutterstock

Gribonika first became interested in science at a young age. My mom and dad would always read to me about great discoveries and about the people who made them, she recounted. These stories sparked her imagination and got her thinking about nature and the world from different perspectives.

I got interested in science to question whats therewhat we can see and what we cant see, Gribonika said. Immunology is heavily focused on microscopy, on the things we dont see just by looking at our skin. But if you ask the right questions and use the right antibody to target the right thing, all of a sudden you see all these interesting things happening in and on the skin.

Gribonika is a native of Latvia, a small northern European country with less than two million people. As her friend Daina Bolsteins, an administrative assistant at NIAID who is also of Latvian descent, noted, Latvia is better known for producing basketball and hockey players, opera singers and symphony conductors than for producing scientists. Gribonika said she hopes her story will inspire other aspiring scientists from her country.

In March, Gribonika headed to Sweden to begin a new chapter as a tenure-track investigator at Lund University.

Her advice to young investigators? Never give up. Remember why you chose this path in the first place, she said.

If the data disproves your hypothesis, follow the data. If the data conflicts, repeat with other methods and protocols. Be cautious. Verify.

Such rigor in research, she said, opens the door to learning new concepts about the human immune system and overall health.

Results will take you to places you never thought of, she said. Theres a lot of novelty out there.

More here:
NIAID Fellow Uncovers the Skins Natural Immunity | NIH Record

Skin Stem Cells Comments Off on NIAID Fellow Uncovers the Skins Natural Immunity | NIH Record | March 1st, 2025

Abstract

Exosomes are tiny extracellular vesicles secreted by most cell types, which are filled with proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, DNA), can be released by donor cells to subsequently modulate the function of recipient cells. Skin photoaging is the premature aging of the skin structures over time due to repeated exposure to ultraviolet (UV)which is evidenced by dyspigmentation, telangiectasias, roughness, rhytides, elastosis, and precancerous changes. Exosomes are associated with aging-related processes including, oxidative stress, inflammation, and senescence. Anti-aging features of exosomes have been implicated in various in vitro and pre-clinical studies. Stem cell-derived exosomes can restore skin physiological function and regenerate or rejuvenate damaged skin tissue through various mechanisms such as decreased expression of matrix metalloproteinase (MMP), increased collagen and elastin production, and modulation of intracellular signaling pathways as well as, intercellular communication. All these evidences are promising for the therapeutic potential of exosomes in skin photoaging. This review aims to investigate the molecular mechanisms and the effects of exosomes in photoaging.

Keywords: Skin photoaging, UV-induced signaling, Stem cell, Exosome

The harmful effects of ultraviolet (UV) irradiation on the skin, the largest organ in the body, have resulted in an increased demand for sun-damaged skin care products. Photoaging is the premature aging of human skin due to continuousexposure to UV radiationleads to significant alterations including, irregular pigmentation, telangiectasias, roughness, deep wrinkles, dryness, rhytides, elastosis, and precancerous lesions. Moreover, photoaged skin is associated with cellular and extracellular changes. These changes include high epidermal thickness, disorganization of collagen fibers, accumulation of dystrophic elastic fibers, cell genomic instability, as well as diminished viability, and morphological changes of keratinocytes and human dermal fibroblasts, all of which contribute to the pathogenesis of skin photodamage [1, 2].

Exosomes are nano-sized vesicles that serve as a subgroup of vesiclesinvolved in cell-to-cell communication, containing bioactive ingredients such as lipids, proteins, and nucleic acids for cell-to-cell communications. Exosomes can be easily endocytosed and transfer their contents to recipient cells. Exosome therapy as a cell-free therapeutic intervention is correlated with lower risks of tumorigenicity and immunogenicity, reduced potential for uncontrolled cell differentiation and cell proliferation compared to stem cell therapy. Exosomes also show promise as vehiclesfor drug or gene delivery [3]. A large number of studies have demonstrated the therapeutic implications of stem cell-derived exosomes (including those derived from bone marrow mesenchymal stem cells, umbilical cord-derived mesenchymal stem cells, adipose-derived stem cells, and pluripotent stem cells) in age-related diseases, tissue regeneration, wound healing, and dermatological conditions [4]. The biological functions of exosomes have mostly been investigated in preclinical studies. For example, exosomal mmu-miR-291a-3p could exert anti- senescence effect in human dermal fibroblasts, through TGF- receptor 2 signaling pathway and promote skin wound healing in aged mice [5]. Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomes which contain a high concentration of growth factors such as epithelial growth factor (EGF), have been found toincrease collagen production and migration ability of normal fibroblasts. These stem cells-derived exosomes penetrate into the epidermis of skin samples in a time-dependent manner and increase collagen I and elastin while decreasing MMP1 expression [6]. Because of the similarity between the molecular mechanism of aging and photoaging, these findings hold promise for the potential use of exosomes in anti-photoaging-related cosmetics or therapeutics for skin rejuvenation and regeneration.. The cosmetic and therapeutic benefits of exosomes for skin care are mediated through their immunomodulatory function, reduction of oxidative stress, decreasing senescence, and stimulation of extracellular matrix (ECM) components production. The aim of this review is to provide an overview of the molecular mechanism of UV-induced skin aging and to highlight the efficiency of exosomes in skin photoaging.

Photoaging is one of the most common skin defects. In the recent years, many studies have been conducted to understand the underlying mechanisms of skin aging. It has been discovered that a multitude of signaling pathways and molecules are involved in regulating this process [7]. In the subsequent section, we will provide an overview of the current understanding of the mechanisms involved in photoaging.

Many inflammatory pathways activated in response to UV radiation contribute to the generation of reactive oxygen species (ROS) and the degradation of collagen and elastin, which are two proteins responsible for skin elasticity and firmness. Interleukin-1 alpha (IL-1) and interleukin-1 beta (IL-1) are proinflammatory cytokines that are suggested to play a role in the photoaging process. In response to UV radiation, these cytokines are produced and contribute to the inflammation and damage caused by ROS. IL-1 and IL-1 can facilitate the breakdown of collagen and elastin by upregulating the expression of matrix metalloproteinases (MMPs), enzymes responsible for the degradation of these proteins [8]. Similarly,cytokine, like IL-6, can contribute to the breakdown of collagen and elastin by increasing the expression of MMPs. Additionally, IL-6 can promote the formation of senescent cells, which are damaged cells that have stopped dividing and can contribute to the aging process [9]. In addition, Toll-like receptors (TLRs), a type of receptor found in the body's immune system [10] are triggered by UV radiation, resulting in a cascade of inflammatory responses in the skin and finally leading to signs of aging [8]. TLR4 signaling pathway may contribute to the increased amount of IL-6 and IL-8 in the senescent skin cells following UV exposure [11]. UV radiation can induce expression of COX-2, which can lead to inflammation and skin damage in the context of photoaging. UV light-induced MAPK pathway can eventually promote COX-2 production [12, 13]. Other pro-inflammatory cytokines, such as TNF- and IL-1, can also enhance COX-2 synthesis [14]. Moreover, a recent study argued suppression of COX-2 can decrease the UV-induced consequences, underscoring the importance of this protein in photoaging [15].

UV radiation causes the production of ROS in skin cells, leading tooxidative stress. This stress causes damage tocellular components such as lipids, proteins, and DNA, which can lead to cellular dysfunction and ultimately contribute to the signs of photoaging, such as wrinkles, age spots, and loss of skin elasticity. The Nrf2/ARE pathway is a key regulator of the cellular response to oxidative stress, and it plays an important role in protecting skin cells from the damaging effects of UV radiation in photoaging. Under normal conditions, NF-E2-related factor-2 (Nrf2) is sequestered in the cytoplasm by its inhibitor protein, Keap1. However, in response to oxidative stress, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it binds to the antioxidant response element (ARE) in the promoter region of genes that encode antioxidant and detoxification enzymes [1618]. This leads to the activation of these genes and the subsequent synthesis of antioxidant and detoxification enzymes, that help neutralize ROS and prevent oxidative damage [19]. It was shown that upregulation of antioxidant enzymes' expression levels in human skin fibroblasts (HSF) via modulation of the KEAP1-Nrf2/ARE signaling pathway enhances cell antioxidant capacity and reduces UVA-induced ROS and lipid oxidation product malondialdehyde (MDA) [20]. Peroxisomes and peroxisomal enzymes also play a crucial role in regulating the levels of ROS. Investigators indicated the efficiency of catalase and superoxide dismutase in photoaging progression collapses significantly [21].

UV can cause various types of DNA damage, including the formation of pyrimidine dimers (such as thymine dimers), which distort the DNA structure and interfere with normal replication and transcription processes. Moreover, it can lead to the generation of reactive oxygen species and indirectly cause nuclear DNA damage. Base-excision repair is responsible for repairing this type of damage, while UVB radiation directly damages DNA and is repaired through nucleotide excision repair [22]. As individuals age, the efficiency of various DNA repair mechanisms, including NER, BER, double-strand break repair, and mismatch repair, declines [23]. This results in a gradual accumulation of DNA damage over time, particularly in intrinsic aging, which can give rise to aging-related traits. UV exposure can exacerbate this process by causing more DNA damage. Concerning photoaging, prolonged exposure to UV radiation can lead to the accumulation of photoproducts in the skin, surpassing its DNA repair capacity [24]. Moreover, evidence suggeststhat UV-induced telomere mutations, shortening, and telomerase dysfunction might facilitate photoaging and cell death progression [23, 25].

In photoaging, the accumulation of DNA damage can trigger the persistent activation of the p53 pathway, which can contribute to the loss of skin elasticity and the development of wrinkles. Additionally, the ATM/ATR pathway is involved in the response to DNA damage. It activates DNA repair mechanisms and can induce cell cycle arrest to facilitate DNA repair. These pathways can also induce apoptosis if the damage is too severe or if the repair mechanisms are overwhelmed [26, 27]. Poly(ADP-ribose) polymerase-1 (PARP-1) is a well-studied nuclear enzyme that belongs to the PARP superfamily. PARP-1 functions as a sensor for DNA damage.. Upon detecting DNA damage, PARP-1 utilizes NAD+as a substrate to add mono-ADP-ribose or poly(ADP-ribose) (PAR) to various acceptor proteins, including PARP-1 itself. Subsequently, activated PARP-1 can induce DNA repair through a base excision repair [28, 29]. However, high UV exposure can also lead to excessive activation of PARP-1 and therefore lead to depletion of the cellular stores of NAD+and ATP, which can contribute to cell death [30].

One of the important mechanisms implicated in thephotoaging of the skin tissue is programmed cell death or apoptosis. It has been shown that there are a vast number of mechanisms underlying this process during photoaging, and many of them still remain unclear. The cascade begins with the dysregulation of crucial apoptosis-related proteins, including Bax, Bcl-xL, PARP, and caspases. [31]. One study discovered that induced deregulation in apoptotic genes, such as p53, caspase-8 and 3, Bax, and Bcl-2 can interestingly enhance anti-photoaging effects by preventing UVB-induced apoptosis [32]. Furthermore, UV might induce upregulation of MAPK pathway-related genes in the chemokine signaling pathwayresulting in oxidative stress and necrotic cell death [33]. On the other hand, it is shown that UV exposure can directly and indirectly (via induced ROS production) activate the mechanism of neutrophil extracellular traps (NET or netosis) which is an immune programmed cell death pathway in that neutrophils release their DNA and sacrifice themselves. Therefore, UV-induced netosis is suggested as a novel pathway that contributes to photoaging progression [34].

Extracellular matrix (ECM) degradation is one of the main hallmarks of photoaging. Exposure to UV radiation can cause damage to the ECM by inducing the production of MMPs, which are enzymes responsible for breaking down collagen and elastin [35]. The stimulation of the MAPK pathway is the primary regulator of UVR-induced MMP upregulation. In addition, ROS generation is essential for UVR-induced MAPK-mediated signal transduction [36]. The UV-dependent MAPK induction results in MMP-1 overexpression followed by type I collagen (COL-1) degradation [37]. Moreover, another study suggested that inhibition of ERK and p38 protects against UVB-induced photoaging by promoting COL-1 accumulation [38].

In the skin, TGF signaling inhibits keratinocyte development and acts as a profibrotic agent in the dermis. In photoaging, chronic UV exposure triggers the TGF1/SMAD3 signaling pathway and leads to metalloproteinase-induced collagen breakdown and photo inflammation. UV irradiation also induces gene alterations in TGF pathway components such as TGFRI, TGFRII, SMAD2, and SMAD4 [39]. Furthermore, several studies support the idea that increased pro-collagen production through TGF-/Smad pathways, and the expression suppression of MMPs by blocking MAPKs, AP-1, and NF-B pathways could exhibit anti-photoaging effects [4043].

Autophagy is a cellular process that involves the degradation and recycling of damaged or dysfunctional cellular components [44]. In the context of photoaging, studies showed that UV exposure can both induce and inhibit autophagy in a context-dependent manner.. Autophagy plays a complex role, with both protective and harmful effects [45, 46]. On one hand, autophagy can help to remove damaged proteins and organelles and can promote cell survival in response to oxidative stress and DNA damage caused by UV radiation. Autophagy can also help to maintain cellular energy homeostasis, which can be disrupted in response to UV radiation [47]. Specifically, exposure to UVB radiation leads to the direct and rapid activation of three proteins including AMPK, UVRAG, and p53, which in turn activate autophagy [45, 48, 49].

Autophagy can be inhibited by UV radiation and subsequent pro-inflammatory signals such as TNF-, IL-1, and IL-6 [50]. This inhibition of autophagy can contribute to the accumulation of damaged proteins and organelles, leading tocellular dysfunction and development of photoaging [51].

Chronic exposure to UVA irradiation decreases the expression of Bach2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) in skin fibroblasts,which increasesthe expression of cell senescence-related genes and enhances UVA-induced photoaging. Conversely, overexpression of Bach2 can decrease the expression of cell senescence-related genes. Bach2 plays a critical role in suppressing UVA-induced cell senescence via autophagy by modulating the expression of autophagy-related genes and directly interacting with autophagy-related proteins. The precise molecular mechanism underlying the connection between Bach2 and autophagy remains unknown, and further studies are necessary to elucidate this signaling pathway [52]. Also, another more recent study revealed that autophagy inhibition can result in higher photodamage in fibroblasts. It was shown that colony-stimulating factor 2(CSF2) can enhance autophagy while decreasing the expression level of MMP-1 and MMP-3. The negative correlation between autophagy and mentioned MMPs supports the importance of autophagy in anti-photoaging response. Moreover, the expression of AKT can influence the activation of autophagy, which is overexpressed along with the JAK2/STAT3 pathway and may contribute to several severe UV-induced consequences [46]. Collectively, the impact of autophagy during photoaging depends on its balance with apoptosis induction, while more studies are needed to investigate the impact of autophagy in photoaging.

Heat shock protein 27 (HSP27), a member of heat shock protein family, has been implicated in various cellular processes, including stress response, apoptosis, and cytoskeletal organization [53]. HSP27 has been shown to interact with several proteins involved in the regulation of oxidative stress, apoptosis, and aging, such as Bcl-2, p53, p21, and p16 after UV exposure [54]. Reduction in HSP27 expression has been associated with increased levels of MMP-1 and MMP-3, along with the downregulation of type I collagen [55]. Furthermore, the suppression of HSP27 expression can partially enhance apoptosis through further activation of p65 and caspase-3 [56]. These interactions can modulate the balance between cell survival and death, ECM degradation, and oxidative stress response in response to UV radiation.

Skin-associated adipose tissue, consisting of dermal (DWAT) and subcutaneous (SWAT) adipocytes, is critical in skin photoaging. In particular, DWAT, located in the reticular dermis of the skin, serves as a unique layer of adipocytes that can extend into the upper dermis and create a "fat bridge" between the skin surface and subcutaneous fat, linking the area directly exposed to UV radiation with the deeper fat layer [57, 58]. However, the turnover rate of DWAT adipocytes exceeds that of SWAT, and long-term excessive exposure to UV radiation can lead to DWAT depletion and skin fibrosis due to adipocyte-myofibroblast transition [59, 60]. This transition results in the replacement of fibrosis with DWAT volume, causing an uneven skin structure and the formation of skin folds [61]. UV radiation induces the activation of the TGF- signaling pathway, which contributes to the conversion of adipocytes to myofibroblasts, resulting in the depletion of DWAT [62].

In addition to DWAT, SWAT also plays a crucial role in skin photoaging [63, 64]. Proinflammatory chemokines (IL-6 and IL-8) deregulation and their regulatory pathways (JAK pathway) due to UV-induction can lead to SWAT depletion and thinning of connective tissue, resulting in skin atrophy and wrinkle formation [65]. Moreover, chronic UV radiation inhibits the differentiation of preadipocytes and reduces the accumulation of triglycerides in mature adipocytes due to the decrease in lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPAR) expression [66]. The decrease in both DWAT and SWAT contributes to the overall deterioration of skin structure and function in photoaging.

Exosomes are a subclass of extracellular vesicles with a size less than<150nm in diameter that facilitates intercellular communication [67]. Exosome biogenesis begins with formation of early endosomes through the invagination of plasma membrane which later generates multivesicular bodies (MVBs) containing Intraluminal Vesicles (ILV) (Fig.1). During maturation of early endosomes to late endosomes or MVBs, the cargoes are incorporated into ILVs. ILVs are formed through the (endosomal sorting complex required for transport) ESCRT-regulated mechanism. The ESCRT is a family of proteins consist of ESCRT-0, -I, -II, -III, and Vps4which are essential for vesicle budding, cargo sorting, and the formation of ILVs [68]. Recent evidence showed there is a second mechanism for exosome formationand cargo sorting in an ESCRT-independent manner which involves proteins such as tetraspanin [69]. The MVBs can fuse with the plasma membrane to release ILVs, which are called exosomes, to the extracellular environment. Exosomes include various proteins that participate in the formation and secretion of vesicles (Rab GTPase), proteins, major histocompatibility complex (MHC) proteins (MHC I and MHC II), tetraspanin family, heat shock proteins, and cytoskeleton proteins. Exosomes may carry other cell-specific proteins which their presence depends on pathophysiological conditions [68, 70].

Exosome are small membrane vesicles that are formed by internalization of plasma membrane and formation of early endosomes. The early endosomes transform to late endosomes through maturation, then late endosomes, which termed as multivesicular bodies (MVBs), undergo inward membrane budding intraluminal vesicles (ILVs). MVBs fusion with the plasma membrane leads to release ILVs, or exosomes, into the extracellular space. Exosomes contain various biomolecules depends on the cell type of origin. Lipids, proteins and nucleic acids are the common molecular constituents of the majority of exosomes [67]. Exosomes are also rich in cytokines, growth factor and antioxidant

The release of exosome is regulated by the SNARE proteins, RABs, and other Ras GTPase proteins. Rab GTPases is the member of Ras superfamily of GTPases and is responsible for the formation, membrane fusion, and secretion of vesicles. There are four Rab GTPase proteins including RAB7, RAB11, RAB27, and RAB35,whichare involved in the formation and release of exosome. SNARE proteins mediate the fusion exosome with the plasma membrane or the membrane of organelles [71]. After fusion with plasma membrane, exosomes are released into the extracellular environment and deliver signals to recipient cells through different mechanisms. They can directly merge with the cell membrane and release their contents, interact with cell surface receptors through exosomal surface proteins, or undergoes endocytic uptake [70].

Cells can release exosomes with different sizes, contents, and functional effects on the target cells. At present, different methods are used to separate distinct subpopulations of exosomes. Among them, ultracentrifugation is the most common method that can separate exosomes based on their size and density. Other methods such as polymer precipitation, size-exclusion chromatography, and immunoaffinity are also used to isolate exosomes [72]. The isolated exosomes are then characterizedby analyzing the exosomal markers. Exosomes contain two types of protein. The first group is the common proteins including tetraspanin family (CD9, CD63, CD81), cytoskeletal proteins (actin, tubulin), heat shock proteins (HSP70, HSP90), and the presence of exosome can be confirmed by identification of these proteins. Other specific proteins are varying depending on the cell of origin, for example exosomes derived from malignant tumors contain tumor antigens, which can be used to determine the origin of exosome, related disease and response to the specific treatment [73]. Besides proteins, exosomes contain lipids, mRNA, and other small RNA such as miRNA and other non-coding RNAs. Exosomes have the ability to transfer their genetic contents into the recipient cells and modify different cellular functions. Moreover, they have the potential to be used as diagnostic biomarkers or therapeutic tools for different pathologies [67].

Some studies have indicated that different cells including stem cells and non-stem cells can release exosomes and exert therapeutic effect against photoaging (Table1), which will be discussed in the next sections.

In vitro and in vivo studies have proved the therapeutic potential of exosomes in amelioration ofskinphotoaging

HSF cells, Kunming mice

UVB-irradiated mice

Human umbilical cord mesenchymal stem cells (HucMSCs) are mesenchymal stem cells that are collected from the different parts of the human umbilical cord. These cells possess the ability to self-renew and differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. HucMSCs exhibit immunomodulatory, anti-inflammatory, and anti-oxidative properties, making them promising candidates for cell therapy and regenerative medicine [83].

Recent studies have investigated the effects of HucMSC-derived exosomes on mitigating the harmful consequences of UV exposure on the skin. Specifically, researchers focused on the role of 143-3, a protein found in HucMSC exosomes, and its interaction with SIRT1. The study demonstrated that HucMSC exosomes containing 143-3 could effectively protect skin cells from UV-induced damage by reducing oxidative stress and inflammation by mediating the SIRT1 pathway [74]. Moreover, these exosomes can enhance the proliferation and migration of HaCaT keratinocytes while inhibiting UVB-induced damage. The findings also show that these exosomes can reduce apoptosis and senescence, increase collagen type I expression, and decrease matrix metalloproteinase (MMP1) expression in photo-aged skin cells [84, 85].

The process of adipocyte development from mesenchymal cells is a multifaceted series of events, both transcriptional and non-transcriptional, that takes place throughout the lifespan of humans. Cells with preadipocyte traits can be derived from adipose tissue in adult individuals and can be grown in vitro. These cells can then be encouraged to differentiate into adipocytes [86].

The role of exosomes derived from adipose tissue-derived stem cells (ADSCs) in preventing photoaging has been extensively studied. Studies indicate that these exosomes effectively inhibit UVB-induced cellular DNA damage through ROS downregulation. Moreover, they can also significantly prevent MMP-1, MMP-3, and COL-3 overexpression and, therefore, protect the ECM integrity. These exosomes may also regulate Nrf2 and MAPK/AP-1 and activate TGF-/Smad pathways upstream of the latter ones [87, 88].

Furthermore, studies have also shown that miR-1246, a highly prevalent nucleic acid in ADSC-derived exosomes, inhibits the MAPK/AP-1 signaling pathway to reduce MMP-1 production and activates the TGF-/Smad pathway, resulting in enhanced pro-collagen type I secretion and an anti-inflammatory impact. In-vivo experiments on Kunming mice demonstrated that miR-1246 might protect against UVB-induced skin photoaging by inhibiting the production of wrinkles, epidermal thickening, and collagen fiber loss. Together, these findings suggest that exosomes derived from ADSCs, particularly miR-1246, play a vital role in the treatment of photoaging by regulating various signaling pathways [75]. Moreover, lncRNA H19, a reach component of ADSC-derived exosomes, shows MMP inhibition and COL-1 production effect on UVB-irradiated mice. It can also sponge miR-138 to target SIRT1, therefore mediating SIRT1 expression and its anti-photoaging impact [76].

Bone marrow mesenchymal stem cells (BM-MSCs) are a type of adult stem cells that have great therapeutic potential in regenerative medicine. Exosomes secreted by BM-MSCs have emerged as a crucial component of their paracrine signaling mechanisms. BM-MSC-derived exosomes contain a variety of bioactive molecules, such as growth factors, cytokines, and miRNAs, that can promote tissue repair and regeneration in various injury and disease models [89].

It is shown that BM-MSCs can mitigate UV-induced oxidative stress and inflammation in a dose-dependent manner and increase cell viability in human dermal fibroblasts (HDFs). BMSCs-exosomes also reduced the expression of MMP-1 and MMP-3 while promoting the expression of COL-1 by reversing MAPK/AP-1 pathway [90]. Moreover, miR-29b-3p, which is found in BM-MSCs-derived exosomes, can participate in reversion of UVB-induced HDF migration suppression, oxidative stress increase, and apoptosis promotion. It is suggested that mentioned miRNA can target MMP-2 and thus prevent COL-1 degradation [77].

Induced pluripotent stem cells (iPSCs) are a type of stem cells that are generated by reprogramming adult cells, such as skin cells, to an embryonic-like state. iPSCs have the ability to differentiate into virtually any cell type in the body and have significant potential for regenerative medicine and drug discovery. iPSCs were first successfully created in 2006 by reprogramming human skin cells using a combination of four transcription factors, including Oct4, Sox2, Klf4, and c-Myc. This discovery was a significant breakthrough in the field of stem cell research and has led to a greater understanding of cellular reprogramming and its potential applications in the future [9193].

It was observed that exosomes derived from human iPSCs (iPSCs-Exo) promoted the proliferation and migration of HDFs under normal conditions. Upon UVB irradiation, HDFs were damaged and overexpressed matrix-degrading enzymes (MMP-1/3), but pretreatment with iPSCs-Exo inhibited these damages. iPSCs-Exo also increased the expression of collagen type I in photo-aged HDFs. Furthermore, iPSCs-Exo significantly reduced the expression of SA--Gal and MMP-1/3 and restored the expression of COL-1 senescent HDFs [78]. SA--Gal is known to be a switch that shifts cells toward senescence fate and is known as an aging marker [94]. Therefore, these results suggest that iPSCs-Exo may have therapeutic potential in the treatment of skin aging.

Human dermal fibroblasts (HDFs) are the main cells in skin derived from MSCs, which play a critical role in extracellular matrix (ECM) remodeling and providing integrity and elasticity to the skin. In the process of skin aging, HDFs proliferation is declined, with decreased collagen production and increased MMPs, resulting in the degradation of the ECM. All of these processes lead to loss of integrity and elasticity and the formation of wrinkles.

Exosomes secreted by human dermal fibroblast cell UVB-irradiated human dermal fibroblasts (UVB-HDFs) are associated with skin photoaging. The analysis of miRNA expression profiling showed the number of dysregulated miRNAs in extracellular vesicles (EVs) derived from UVB-irradiated HDF. Upon UVB-irradiation, expression of miRNA-22-5p was significantly increased in HDF cells and their derived EVs, and can be transferred to other HDFs cells. further analysis showed that miRNA-22-5p upregulation promotes photoaging by targeting growth differentiation factor 11 (GDF11), a protein that protects HDF cells from photoaging [79]. In another study, exosomes derived from three-dimensional (3D) aggregation of HDF cells or spheroid induced collagen synthesis and reduced inflammation in a photoaged skin of mice model. It was hypothesis that miR-133a and miR-223 were upregulated and miR-196a was downregulated in the exosome derived from 3D cultured HDF spheroids, which might inhibit MMP expression, enhance collagen restoring and replacing and activate TGF- signal pathway. Thus 3D HDF-XOs can be used as an effective approach to prevent skin photoaging [80].

Human umbilical vein endothelial cell(HUVEC) is a model cell line to study endothelial cells and can be derived from umbilical cords. Recently, Ellistasari et al. have conducted an in vitro study to investigate the effect of exosomes derived from HUVEC cells in attenuating skin photoaging. They observed that Exo-HUVEC can markedly increase cell proliferation and collagen synthesis in UVB-irradiated fibroblasts, Moreover, Exo-HUVEC can decrease MMP expression which leads to inhibiting collagen degradation in the photoaged cell line model. This source of exosome has the potential efficiency to prevent and treat skin photoaging [81]. Exosome sources are not limited to animal cells. Interestingly, natural exosomes, that originate from plants or other organisms, contain more bioactive molecules than those derived from animal cells. In the study by Han et al. exosome-like nanovesicles derived from a medicinal mushroom, Phellinus linteus (PL), has been shown to have anti-aging and anticancer effects. The fungi exosome-like nanovesicles (FELNVs) can protect skin from UV-induced photoaging. It was shown that fungal EVs are enriched with different miRNAs including miR-CM1-5, and among them miR-CM1 could protect HaCaT cells from UV-induced damage. MiR-CM1 exerts a protective effect through reduction of aging-related markers such as SA--Gal, ROS level, MMP1, and COL1A2 expression. Mical2 was known as a direct target of miR-CM1 which is involved in the regulation of age-related processes [82].

In recent years, exosomes have been exploited as a novel candidate for treatment of many diseases including central nervous system disorders, cardiovascular diseases, and cancer. Under the pathophysiological condition, biological components of exosomes are changed, reflecting the alteration in the cell functions. The alteration in the exosomal components can be served as diagnostic and prognostic biomarkers in many diseases from cancer to aging [95]. Exosomes can be extracted from cell culture, tissues, and biological fluids including plasma, serum, urine, etc. [96]. Exosomes can act locally or transported to distant tissues via body fluids and modulate the function of target cells [97].

Mesenchymal stem cells are multipotent stem cells that that possess a the high ability to release exosome and can be extracted from bone marrow, umbilical cord, and adipose tissue [98]. Exosome therapy as a cell-free strategy offers severaladvantages of small size, no risk of tumorigenicity, and long-term storage making it a potentially safer and more effective alternative to stem cell therapy [3]. Also, exosomes show great promises as the drug delivery carrier due to high stability, biocompatibility, and low immunogenicity compared to virus-based delivery and other non-viral methods. However, there are still some challenges for the application of exosomes in clinics such as low yield of isolation [72].

Preclinical investigations showed that exosomes may have a therapeutic role in aging and other age-related diseases [99]. Cellular aging is due to various biological changes including, epigenetic alteration, genomic instability, senescence, oxidative stress, mitochondrial decline, and dysregulation of intracellular communication [100]. Some studies have demonstrated the therapeutic potential of exosome in preclinical models of age-related diseases such as Alzheimers, Type 2 diabetes (T2DM), osteoarthritis, chronic kidney disease, etc. [99].

Exosomes have many beneficial effects for skin care as they contain various biological molecules that can help to promote skin repair and regeneration [101]. Previous studies have demonstrated that exosomes and other EVs have therapeutic benefits in skin defects such as wound and aging. Most of these studies on the potential use of exosomes in skin repair have been conducted in animal models. For example, it was found that bioengineered exosomes loaded with miRNA-542-3p, derived from bone marrow MSCs (BMMSCs), could promote cell proliferation, collagen synthesis, and wound closure in mice models. Currently, the clinical applicability of exosome-based therapy is limited to skin wound repair [102]. To date, there is no clinical trial has been conducted on exosome in photoaging.

Exosomes are able to deliver various bioactive compounds into the skin cells, which can effectively delay skin aging and inhibit photoaging signatures. These nanovesicles would be artificially engineered with desired biological molecules [4, 103]. Exosomes can be delivered to skin through various invasive and non-invasive methods. In the non-invasive treatment exosomes are incorporated into topical creams, serums, oils, and masks to cover and protect skin [104]. Exosomes can also be incorporated into bioactive polymeric materials like hydrogel, allowing for sustained release, pH maintenance, and enhanced regenerative potential [105]. Local injection is the invasive type of treatment in which anti-aging molecules are injected into the inner layer of skin to enhance therapeutic effects and overcome skin barrier. Subdermal injection of ADSCs has been demonstrated to be effective in reducing anti-photogaing effects through ECM remodeling and neoelastogenesis (Fig.2) [106]. Since MSCs-derived exosomes represent biological activity corresponding to these stem cells, similar and even more effective therapeutic outcome is expected in exosome-based therapeutic protocols. Local injection provides more effective skin treatment compared to topical products due to skipping skin barrier [104]. The stability of exosomes is critical both before and after injection. Exosome lyophilization is often used to increase stability and maintain the activity of biological molecules. This method involves in dehydration and drying of exosome under vacuum condition at low temperature, resulting in their longer storage without loss of activity [107]. Systemic treatment is another method previously used to deliver exosomes through intravenous injection. It has been shown that topical application of exosome combined with intravenous injection effectively accelerates non-diabetic wound healing [108]. Exosomes stimulate collagen production in photoaged skin and reduce the appearance of pigmentation [4]. Moreover,photoaging is associated with a greater risk of malignant tumors like melanoma [109]. Thus, treatment of skin photoaging has important clinical significance and exosome-based therapy could be a helpful method not only in cosmetic application but also in skin cancer prevention.

Exosomes derived from different types of stem cells can play an important role in reducing photoaging by entering the target cells and transferring their contents. UV radiation induce generation of reactive oxygen species (ROS), leading to DNA damage, activation of inflammatory pathway, production of matrix metalloproteinases (MMPs) and degradation of collagen fibers. Skin photoaging is characterized by structural change, appearance of wrinkles and pigmentation (Reviewed in [7]). Exosomes derived from stem cells can be served as novel treatment option for skin repair and regeneration. Administering exosomes in the form of lyophilized injection may be one of the effective approaches to repair photo-damaged skin

Photoaging is a prominent manifestation of skin aging characterized by the appearance of mottled pigmentation, fine lines, and wrinkles. The main molecular mechanisms of photoaging are accumulation of reactive oxygen species, cellular senescence, inflammation, and collagen degradation. Targeting these pathways through novel therapeutics is an intriguing area of study in regenerative medicine. Exosomes are able to regulate multiple cellular processes due to their important role in cellular communication. In the last years, exosomes have emerged as a novel therapeutic option for treatment of many diseases. This review aims to summarize the current findings on the roles of exosomes, particularly those derived from stem cells, in the context of skin photoaging. While most studies investigating the use of exosomes in treating skin defects have been conducted at the preclinical level, additional research is needed to evaluate the therapeutic potentials and clinical values of exosomes in the field of skin treatment medicine.

None.

Reactive oxygen species

Interleukin

Matrix metalloproteinase

Toll-like receptor

Mitogen-activated protein kinase

Cyclooxygenase-2

Tumor necrosis factor-alpha

Nuclear factor kappa B

IB kinase

Inhibitory kappa B

NF-E2-related factor-2

Antioxidant response element

Deacetylase silent information regulator 1

PAR coactivator-1

Human skin fibroblast

Malondialdehyde

Poly(ADP-ribose) polymerase-1

Neutrophil extracellular traps

Extracellular signal-regulated kinase

C-Jun amino-terminal kinase

Collagen

AMP-activated protein kinase

UV radiation resistance-associated gene

Tuberous sclerosis complex

BTB and CNC homology 1, basic leucine zipper transcription factor 2

Broad complex, tramtrack, bric-a-brac/poxvirus, and zinc finger

Heat shock protein

Dermal white adipose tissue

Subcutaneous white adipose tissue

Acetyl-CoA carboxylase

Fatty acid synthase

Stearoyl-CoA desaturase

Sterol regulatory element binding proteins

Peroxisome proliferator-activated receptor

A.HN., N.M. and M.HS. wrote the manuscript. MH.S. conceived the original idea and drafted the manuscript. All listed authors read and approved the final manuscript.

None.

Not applicable.

The authors declare no competing interests.

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