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].

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