Todays ecosystem is based around living volunteers, Ossiums CEO and cofounder, Kevin Caldwell, says. While the US organ donor system has existed for decades, bone marrow has never been regularly collected from those deceased donors in the same way that hearts, lungs, kidneys, and livers have. Nobody had come up with an efficient way of obtaining the cells from deceased donors or cryopreserving them at scale so they can be stored until needed.

Ossium CEO and cofounder Kevin Caldwell.

Unlike a solid organ, you cant just transplant bone marrow into the nearest person who is roughly the right size who needs it, Caldwell says. You really have to have a close genetic match between the donor and the recipient.

The new method of stem cell harvesting, via apheresis, doesnt work well in deceased people because it relies on blood pressure. Based on previous research conducted at the University of Pittsburgh and Johns Hopkins University, Ossium developed a way to extract bone marrow from the spinal column, a part of the body that typically went unused. The company has partnered with US organ procurement organizations to recover spinal columns from cadavers and ship them to the companys facility in Indianapolis. There, bone marrow is extracted and cryopreserved in liquid nitrogen vapor at about 190 degrees Celsius.

Caldwell says Ossium has processed thousands of donors since the company was founded in 2016. (The exact number of donors in the bank is proprietary, he says.) Ossiums frozen bone marrow has now been given to three people in total, including the Michigan woman, with a fourth transplant scheduled soon.

Robert Negrin, a professor of medicine at Stanford University and vice president of the American Society of Hematology, calls the transplants an important milestone, but whether the technique will be useful for cancer patients remains to be seen. We have other options that work pretty well, he says, referring to partially matched donor transplants and cord blood transplants. But there are always situations that could fall through the cracks.

Negrin sees potential for deceased donor bone marrow transplants to help organ transplant patients, who currently must take immunosuppressive drugs for the rest of their lives to avoid their immune system attacking the new organ. But because immune cells originate in the bone marrow, if they could receive a marrow transplant from the same donor, Negrin says patients couldin theorygo off immunosuppressive drugs.

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November 15th, 2024

Hematopoietic Stem Cells and Their Niche in Bone Marrow

By daniellenierenberg

Abstract

Extensive research has explored the functional correlation between stem cells and progenitor cells, particularly in blood. Hematopoietic stem cells (HSCs) can self-renew and regenerate tissues within the bone marrow, while stromal cells regulate tissue function. Recent studies have validated the role of mammalian stem cells within specific environments, providing initial empirical proof of this functional phenomenon. The interaction between bone and blood has always been vital to the function of the human body. It was initially proposed that during evolution, mammalian stem cells formed a complex relationship with the surrounding microenvironment, known as the niche. Researchers are currently debating the significance of molecular-level data to identify individual stromal cell types due to incomplete stromal cell mapping. Obtaining these data can help determine the specific activities of HSCs in bone marrow. This review summarizes key topics from previous studies on HSCs and their environment, discussing current and developing concepts related to HSCs and their niche in the bone marrow.

Keywords: hematopoietic stem cells, hematopoietic progenitor cells, bone marrow microenvironment, niche

Blood is a bodily fluid that delivers oxygen and nutrients to cells while collecting and transporting carbon dioxide and waste products produced by cellular metabolism [1]. Blood consists of plasma (a liquid component), red blood cells, white blood cells, and platelets. Hematopoiesis is the biological process through which blood and immune cells are produced [2] (Figure 1). Hematopoietic stem cells (HSCs) in the bone marrow are responsible for continuously replenishing these cells due to their limited lifespan [3]. HSCs occupy the highest position in the hierarchy of hematopoietic cells. The HSC niche in bone marrow is a specialized microenvironment that regulates the maintenance and activity of HSCs [4]. This niche governs self-renewal and differentiation of HSCs, ensuring the continual maintenance of hematopoiesis [5]. The bone marrow microenvironment was first introduced as a niche for HSCs in the 1970s [6]. The niche supplies the necessary components for the self-renewal and differentiation of HSCs. Additionally, the niche controls the states of rest and progression at various stages of the cell cycle in stem cells [6] (Figure 2). It also communicates crucial information to stem cells regarding the surrounding tissue, influences the development of stem cell offspring, and helps prevent genetic mutations [7]. Numerous studies have revealed the significance of HSCs and their niche, leading to a better understanding of their relationship [7,8,9,10,11].

Hematopoietic stem cell (HSC) regulation in steady-state and hematological malignancies. This image shows the features of HSC regulation between normal conditions and hematological malignancy. In normal hematopoiesis, HSCs are activated in response to signals from the bone marrow microenvironment. Upon activation, HSCs undergo proliferation to increase their numbers and develop into multipotent progenitors (MPPs). MMPs can evolve into more committed lymphoid/myeloid progenitors and their respective sub-progenitors (e.g., GMP, MEP, etc.). These progenitor cells undergo further differentiation and maturation to give rise to the diverse range of blood cell types found in circulation. Each cell in the hematopoietic process can be distinguished by differentiation markers. This tightly regulated process of activation, proliferation, and differentiation ensures the continuous replenishment of blood cells to maintain homeostasis. When the HSCs and the progenitors within the developing HSCs become damaged, they can transform into leukemic stem cells (LSCs). LSCs possess self-renewal capabilities and aberrant differentiation, giving rise to leukemic blasts that result in leukemia. CLP: Common lymphoid progenitor. CMP: Common myeloid progenitor. GMP: GranulocyteMacrophage progenitor. MEP: Megakaryocyteerythrocyte progenitor. Pro-B: Progenitor cell-B. Pro-T: Progenitor cell-T. Pro-NK: Progenitor cell-NK. Pro-DC: Dendritic progenitor cell. MncP: Monocyte progenitor. GrP: Granulocytic progenitor. EryP: Erythrocytic progenitor. MkP: Megakaryocyte progenitor. NK cells: Natural killer cells.

An image showing bone marrow microenvironment with their components. It shows two BM niches, two bone marrow niches, and the endosteal and vascular niches. The endosteal niche and vascular niche are two crucial microenvironments within the BM. The endosteal niche, located near the bone surface, provides a specialized environment for hematopoietic stem cells (HSCs) to reside and self-renew. The osteoblast is considered the most important cell in the endosteal niche; hence, it is also referred to as the osteoblastic niche. In contrast, the vascular niche, adjacent to blood vessels, supports HSCs by supplying nutrients and signaling molecules necessary for their proliferation and differentiation. It is composed of endothelial cells lining the blood vessels, as well as pericytes and smooth muscle cells surrounding them. Together, these niches play integral roles in regulating the maintenance and function of HSCs in the bone marrow. CAR cell: CXCL12-abundant reticular cell. OPN: Osteopontin. ANG1: Angiopoietin-1, SCF: Stem cell factor.

Due to global advancements in aging research and the increase in life expectancy over the past 150 years, studies on the physiological changes that occur in organisms as they age have made substantial progress [12,13]. Aging is characterized by a progressive decline in the function of many organs and tissues that, in some cases, can contribute to the development of cancer [14]. The hematopoietic system undergoes alterations with age, which affects the performance and number of HSCs and the composition of blood cells [15], increasing the likelihood of acquiring age-related blood illnesses such as anemia, a weakened immune response, and blood cancer. After a defined period, blood cells undergo differentiation and maturation and are eventually destroyed, preserving the equilibrium state. Hematological disorders are medical ailments characterized by an imbalance in homeostasis [10]. Hematopoietic tissue cancer (blood cancer) is a malignancy that originates in bone marrow [8] and is characterized by the excessive growth of abnormal blood cells [16]. These disorders are due to abnormalities in HSCs, the initiating cells in the hematopoietic system. Therefore, targeting only specific cells while minimizing damage to normal cells remains challenging [17,18]. Consequently, stem cell therapy is emerging as a promising alternative for treating hematological diseases, including those related to aging.

Stem cell therapy is highly regarded for its potential in treating not only blood-related diseases but also for regenerating damaged tissues and organs. Stem cells used in related research encompass various types, including adult stem cells such as HSCs and mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) created by reprogramming somatic cells back to a pluripotent state [19,20]. MSCs, being multipotent stromal cells, exhibit the capacity to differentiate into a variety of cell types, including bone, cartilage, and adipocytes [20,21,22,23]. Consequently, numerous research findings have suggested their therapeutic potential in diverse diseases such as cartilage regeneration [24,25] and neurological disease recovery [25,26,27,28]. ESCs present immense therapeutic promise, as they can differentiate into all cell types in the body [29,30]. However, research in this domain is constrained by ethical dilemmas surrounding the extraction of stem cells from embryos [19]. iPSCs are anticipated to circumvent these ethical issues while offering utility akin to ESCs. Nonetheless, challenges persist in the reprogramming process, and uncertainties exist regarding their stability [19]. Despite active research and reporting on the therapeutic potential of stem cell therapy, many facets of stem cell biology remain unexplored, including fundamental mechanisms governing stem cell behavior and their interactions with the host environment. Consequently, stem cell therapy has not yet attained widespread adoption as a standard treatment. This review focuses on HSCs and their microenvironment to enhance our understanding of stem cell therapy, especially hematopoietic stem cell therapy.

HSCs are a rare population of multipotent cells, responsible for replenishing all blood cell types throughout an individuals lifetime. They have the unique ability to self-renew and differentiate into several types of blood and immune cells. This process, which produces all types of blood cells, is called hematopoiesis (Figure 1) [9]. HSCs produce hematopoietic progenitor cells through differentiation, which differentiate further to produce blood and immune cells [1]. However, hematopoiesis is a highly regulated process and typically unidirectional; once HSCs differentiate into hematopoietic progenitor cells, they cannot regenerate into HSCs [1]. Additionally, HSCs are used in transplantation therapy after irradiation to treat patients with blood cancer [19]. Unlike solid cancers, which can be selectively targeted and treated, blood cancers present significant challenges for treatment with conventional chemotherapy and radiation. For this reason, HSC transplantation remains one of the most effective and promising approaches, with significant ongoing research focusing on its potential [10].

HSCs predominantly reside in a specialized microenvironment within the bone marrow, known as the endosteum [2,9]. In this niche, HSCs remain dormant under stable conditions. When blood cells decrease due to stressors, such as bleeding, illness, or radiation, HSCs activate and reorganize the hematopoietic system by proliferating and differentiating into new cell types [1]. The equilibrium between the quiescent state and the division of HSCs is crucial for maintaining normal hematopoiesis. If this equilibrium is not adequately regulated, HSCs may decrease in number or give rise to blood malignancies such as leukemia (Figure 1). Thus, the equilibrium between the dormant and active phases of HSCs is tightly controlled by both internal and external mechanisms.

Blood is an essential regenerating tissue that is susceptible to changes and deterioration with age [12,13,31]. Aging is accompanied by various clinically significant conditions that affect the hematopoietic system [14], including a decline in the adaptive immune system, an increased occurrence of specific autoimmune diseases, a higher prevalence of hematological malignancies, and an increased likelihood of age-related anemia [32]. An age-related decline in the functional capacity of HSCs has been widely recognized in studies conducted on mouse models [33]. When comparing young HSCs to old ones, the latter exhibit a preference for the myeloid lineage and have a reduced ability to regenerate when transplanted [33]. In addition, like many other tissues, the hematopoietic system is more likely to develop cancer with age, including a higher incidence of chronic and acute leukemia [14]. Given that myeloid leukemia is more common in older individuals and juvenile leukemia typically affects the lymphatic system, age-related alterations in HSCs may directly influence the development of disorders associated with blood cell formation [15]. Aged HSCs show increased expressions of genes implicated in the progression of myeloid leukemia, such as AML, PML, and ETO. Alternation of these gene expressions during normal hematopoiesis can result in impaired self-renewal capacity of HSC, heightened susceptibility to DNA damage, and aberrant differentiation potential. These alternations on HSCs are characteristic features of aged HSCs. Consequently, they are deemed suitable targets for investigating HSC aging and comprehending the molecular mechanisms underlying age-related hematopoietic dysfunction and leukemogenesis [32,34,35,36,37,38].

Multiple studies have documented the deterioration of HSCs in older mice, although the specific molecular processes responsible for this aging phenomenon remain unclear [14,15,31,32,33]. The aging of HSCs is limited by their diversity. The purity of HSCs isolated using flow cytometry has consistently been poor, indicating that the population becomes more heterogeneous as individuals age [15]. Ongoing research aims to identify specific subsets of HSCs that contribute to the aging phenotype [11]. This is achieved through the examination of age-dependent diverse pools of HSCs using single-cell bone marrow transplantation, flow cytometry, and single-cell transcriptome sequencing [15,32,39]. Specifically, HSC clones that undergo myeloid differentiation progressively occupy the HSC reservoir with age [39]. In this aspect, multiple research findings have been reported concerning the correlation between clonal hematopoiesis and aging [40]. Clonal hematopoiesis (CH) is a condition characterized by the expansion of specific HSC clones that acquire somatic mutations (e.g., DNMT3A, TET2, and ASXL) [41,42]. These mutations are thought to confer a selective advantage to HSCs, leading to the predominance of these clones in the blood system and allowing them to outcompete normal HSCs and expand clonally. While the specific signaling pathways involved in this process may vary depending on the gene and context, some common themes have emerged. For example, mutations in DNMT3A [43,44], TET2 [45,46,47], and ASXL1 [48] are known to affect epigenetic regulation, leading to alterations in gene expression patterns and cellular differentiation pathways [42,49]. Additionally, these mutations may impact other signaling pathways related to cell survival, proliferation, and self-renewal [48]. However, the exact signaling pathways or mechanisms through which these mutations lead to clonal expansion are still under investigation and continue to be an active area of research. This phenomenon becomes increasingly common with age and is associated with a higher risk of hematologic malignancies and cardiovascular diseases [41,50,51]. Research indicates that approximately 1020% of individuals over 70 years old exhibit clonal hematopoiesis, highlighting its prevalence in the elderly population.

CH not only alters the composition of the hematopoietic system but also impacts the bone marrow microenvironment, known as the niche, which is crucial for maintaining HSC function and homeostasis. Aging induces significant changes in the bone marrow niche, including a decline in the number and function of MSCs, osteoblasts, and endothelial cells [41,52]. These alterations, coupled with the production of elevated levels of inflammatory cytokines such as IL-6 and TNF- by mutant HSCs and the aging niche, create a pro-inflammatory and oxidative stress environment [47,53,54]. This environment promotes the expansion of CH, impairs normal HSC function, and decreases the secretion of essential factors for HSC maintenance, thus exacerbating the proliferation of clonal HSCs and diminishing the niches ability to support normal hematopoiesis. Although there have been numerous reports on the heterogeneity of HSCs associated with aging, our understanding of the effects of aging remains uncertain, and requires further investigation.

A recent study investigated the functional alterations that occur in aged HSCs within the mitochondrial metabolic milieu [12,13,14]. Specifically, the properties and roles of young and aged HSCs are influenced by the mitochondrial membrane potential within these cells [55]. Researchers reversed aging in old mice by manipulating the mitochondrial membrane potential of aged HSCs using the antioxidant Mito-Q [31]. Clinical utilization of Mito-Q is a possible preventative measure and treatment for age-related blood disorders.

HSCs typically reside in the bone marrow (BM), which is composed of various components, including bone, blood vessels, and other cells and substrates filling the spaces between them [2]. This BM microenvironment, known as a Niche, provides a structural framework and communication networks to HSCs [2,7].

This microenvironment can control the state of HSCs by direct or indirect interactions and safeguard them from sustaining their undifferentiated state [2,7,9]. It engages HSCs to control their growth and specialization through distinct signal transduction processes, resulting in regular hematopoiesis [7]. Recent advancements in single-cell analysis techniques have revolutionized our understanding of the BM niche, shedding light on its cellular composition, spatial organization, and dynamic interactions with HSCs. One of the key insights gleaned from single-cell analysis is the dynamic nature of the BM niche [56]. Studies have revealed the presence of specialized niches within the BM, each tailored to support specific stages of hematopoietic development [57,58]. Moreover, single-cell analysis has unveiled the plasticity of niche cells, demonstrating their ability to dynamically respond to extrinsic signals and adapt to changing physiological conditions [59,60]. Furthermore, single-cell analysis has provided insights into the spatial organization of the bone marrow niche, uncovering intricate spatial relationships between niche components and HSCs. Spatial transcriptomics techniques have revealed specialized niches localized within specific anatomical regions of the BM, highlighting the importance of spatial context in regulating hematopoietic function [58,61,62,63].

Depending on their spatial location, niches can be divided into an osteoblastic niche, which is the area near the endosteum, and a vascular niche, where blood vessels and surrounding matrix exist in the BM [58]. In addition, various immune cells derived from HSCs (including T/B lymphocytes, macrophages, natural killer cells, and dendritic cells) or the stromal cells contribute to configuring the BM microenvironment. These cells interact with HSCs, participating in the regulation of their state. Non-cellular substances can also serve as nutrients for HSCs, providing essential support for their growth and maintenance. These substances may include growth factors, cytokines (e.g., SCF, interleukins, CXCL12), and extracellular matrix components present in the BM microenvironment. By interacting with HSCs, these non-cellular factors play a crucial role in regulating hematopoiesis and maintaining stem cell homeostasis.

The vascular niche is composed of endothelial cells and perivascular stromal cells (such as pericytes and smooth muscle cells) that make up blood vessels [64,65,66]. They provide structural support and produce niche factors essential for HSC maintenance, proliferation, and differentiation. Additionally, the extracellular matrix surrounding these niche cells serves as a dynamic scaffold that facilitates cellular interactions and regulates the release and localization of signaling molecules [67,68].

Vasculogenesis can be categorized into two stages: the embryonic and adult stages [2,9]. During the embryonic stage, there is a significant level of contact between HSCs and endothelial cells [69]. Hematopoietic and endothelial cells are derived from hemangioblasts, multipotent progenitor cells, during the embryonic stage [70]. Endothelial cells expressing RUNX1 can produce HSCs in the aorta, gonad, mesonephros, and placenta [71]. Both endothelial and hematopoietic stem cells co-express CD31, CD34, CD133, FLK1, and TIE2 [72]. HSCs release angiopoietin-1 (ANG1), which stimulates the growth of new blood vessels during angiogenesis [73]. Additionally, endothelial cells provide a similar microenvironment for HSCs as well as neural stem cells. In the hippocampus, neural stem and endothelial cells that generate fibroblast growth factor (FGF), another angiogenesis-promoting substance, are close to each other [74].

However, the precise nature of the interaction between endothelial cells and bone marrow HSCs in the adult stage remains unclear. BM-derived endothelial progenitor cells participate in postnatal angiogenesis [75]. A conceptual framework for the vascular environments in bone marrow has been suggested, wherein the activation of MMP9 expressed in the osteoblast region results in the separation of the Kit ligand from the cell membrane of stromal cells in the BM. Subsequently, the soluble Kit ligand stimulates the initiation of the cell cycle and enhances the activity of HSCs [76]. Thus, HSC activity, proliferation, and differentiation occur in the vascular niche within the BM [69]. Vascular endothelial growth factor (VEGF) and ANG1 are angiogenic factors that play crucial roles in preserving HSCs [77]. VEGF controls the development of blood vessels and hematopoiesis and regulates hematopoietic stem cells through an internal autocrine loop [78]. HSCs remain inactive in osteoblastic niches, whereas both hematopoietic stem and progenitor cells undergo division in vascular habitats. Hematopoietic cell migration commences in stem cells located in the osteoblast niche where they then proliferate, differentiate, and ultimately mature [7]; cells migrate toward the vascular niche via this process.

To maintain hematopoietic homeostasis, the process of homing, wherein hematopoietic stem and progenitor cells (HSPCs) circulating through the blood return to the BM niche, is also essential [79,80,81]. In this process, HSPCs directly interact with the endothelium via cellcell adhesive interaction. Sinusoidal endothelial cells express adhesion molecules, including P-selectin (CD62P), E-selectin (CD62E), and vascular cell adhesion molecule-1 (VCAM-1 or CD106). Several receptors for these molecules are expressed in HSPCs, including P-selectin glycoprotein ligand-1 (CD162) and CD44, along with other less well-defined E-selectin receptors. Additionally, receptors for VCAM-1, such as integrins 41, 47, and 91, are also expressed.

The other components such as pericytes and smooth muscle cells also play an important role in regulating the behavior of HSCs [82,83]. Leptin-receptor-positive (LepR+) cells and CXCL12-abundant reticular (CAR) [82] cells are well-established cells that secrete growth factors essential for the maintenance of HSCs. They are located along the blood vessels of mainly the sinusoids, playing a crucial role in regulating vascular stability and function. CXCL12 and SCF from them are key factors for HSC proliferation [84]. This was confirmed through experiments deleting CXCL12 secreted by LepR+ cells and CAR cells. Deletion of CXCL12 in these cells results in the removal of all quiescent and serially transplantable HSCs from adult bone marrow. This occurs because signaling with CXCR4, receptors on HSCs, is reduced, demonstrating that CXCL12 from LepR+ cells and CAR cells play a central role in the signaling that maintains the pool of HSCs [85].

Conversely, Nestin-positive (Nes+) cells found exclusively around arterioles provide support, contrasting with perivascular cells around sinusoids [86]. Nes+ cells also secrete soluble factors like CXCL12 and SCF, which tend to drive quiescent HSCs into early hematopoietic stages and promote HSC activation, leading to differentiation [87].

Osteoblasts, layering the endosteal bone surface and providing an osteoblastic niche to HSCs, regulate hematopoiesis [7,88]. They provide a supportive environment for HSCs, regulating their self-renewal, differentiation, and quiescence. Osteoblasts produce niche factors and adhesion molecules that interact with HSCs, influencing the maintenance of HSCs in a dormant state and their activation in response to hematopoietic demand [89]. Osteoblasts have a critical role in the regulation of the physical location and proliferation of HSCs by expressing osteopontin (OPN). OPN specifically binds to beta1 integrin expressed on HSCs [90]. The other key factor expressed in osteoblasts is angiopoietin-1 (ANG1). Interaction of Tie2 and ANG1, the receptor of ANG1 expressed on HSCs, vital for maintaining HSCs in the quiescent state, preserves their long-term self-renewal potential and prevents exhaustion [39]. This signaling helps to retain HSCs in the bone marrow niche and prevents their premature differentiation or migration [91,92,93].

Through long-term in vivo labeling with 5-bromodeoxyuridine (BrdU), most HSCs divide [94]. However, some HSCs were found to be dormant, retained their labels, and remained dormant for several months. Therefore, bone marrow cells can be classified into resting and dividing HSCs. Resting HSCs are located close to osteoblasts [7]. Using Bmpr1a KO mice, Zhang et al. showed that N-cadherin+ spindle-shaped osteoblasts resemble HSCs with a slow cell cycle [94]. Their study revealed that osteoblast cells expressing N-cadherin in the bone marrow act as nests for HSCs, and that an increase in the number of N-cadherin+ cells is associated with an increase in HSCs. Additionally, Visnjic et al. showed that hematopoiesis is suppressed in osteoblast-deficient mice [95]. Thus, it was confirmed that defects in HSC osteoblasts inhibit hematopoiesis. The Notch signaling pathway, characterized by membrane-bound ligands, regulates cell fate determination across various systems, including the self-renewal of HSCs [96,97,98,99,100]. In the study by Calvi et al. [101], they found that PPR-stimulated osteoblasts express a high level of Notch ligand jagged 1 using the transgenic mouse of PTH/PTHrP receptors (PPRs). In response, the activation of the Notch1 intracellular domain (NICD) in Lin-Sca-1+c-Kit+ HSCs increased. Additionally, when HSCs were long-term co-cultured with a Notch cleavage inhibitor, the support for HSCs observed in transgenic stroma decreased to a similar level to their isotype control. Another study, using RAG-1-deficient mice essential for V(D)J recombination and lymphocyte development, showed that Notch1 activation leads to inhibition of HSC differentiation [98]. This confirms that interaction between osteoblasts and HSCs via the Notch pathway plays a crucial role in regulating HSC behavior within the bone marrow niche.

In addition to spatially distinct osteoblastic and vascular niches, stromal cells and immune cells play roles within the microenvironments of HSCs in bone marrow [62,63,102,103,104]. They can either directly interact with HSCs or regulate them indirectly by secreting soluble factors such as growth factors, cytokines chemokines, and other signaling molecules.

Macrophages in the bone marrow play a crucial role in the formation of HSCs [63,105,106,107,108,109,110,111]. CD169+ macrophages, associated with the clearance of blood-borne pathogens and regulation of immune responses, play a crucial role in maintaining the quiescent state of HSCs [105]. They interact with Nestin-positive (Nes+) cells to promote the transcription of CXCL12 and other factors (such as HSC maintenance and retention factors ANG, KITl, VCAM1) essential for HSC maintenance. Depletion of macrophages leads to the loss of these factors and subsequent egress of HSCs from the bone marrow [105,106]. A subset of macrophages called Osteomacs reside adjacent to osteoblasts and megakaryocytes along the bone lining, distinct from osteoclasts. These osteomas have been identified to play crucial regulatory roles in modulating osteoblast function. Their interaction with osteoblasts is essential for the low-level activation of nuclear factor B (NF-B) in osteoblasts, enabling them to maintain HSCs through appropriate chemokine signaling. Furthermore, the presence of megakaryocytes supports the function of osteomacs, and their synergistic interactions with osteoblasts contribute to the regulation of HSC repopulating potential, as evidenced by transplantation assays [107,108,109,110,111]. Although significant progress has been made in understanding the role of macrophages in HSC behavior [106], the specific signaling pathways and the diverse functions associated with macrophage heterogeneity are not yet fully understood. Therefore, ongoing additional studies are needed to fully elucidate the multifaceted roles of macrophages in hematopoiesis and their potential therapeutic applications.

Megakaryocytes also govern the viability of HSCs [112,113,114]. Megakaryocyte removal from the bone marrow leads to an increase in the number of HSCs. HSCs exhibited a compensatory increase in mice experiencing bleeding. However, this compensatory increase is restricted when blood cells are introduced into the bloodstream [113]. Megakaryocytes have been suggested to restrict the proliferation of HSCs in two ways. The first mechanism involves the production of CXCL4 by megakaryocytes, which inhibits HSC proliferation [112]. The second mechanism involves the action of TGF, which controls the inactive state of the HSCs [113]. Additionally, megakaryocytes influence myeloid-biased HSC activity and act as a physical barrier to HSC migration. Thrombopoietin (TPO) production by megakaryocytes further regulates hematopoietic activity. Depletion of megakaryocytes in mice resulted in decreased megakaryopoiesis, alongside lower numbers of HSCs and reduced HSC quiescence [115,116,117,118].

Chemokines, also known as chemo-attractant proteins, play crucial roles in regulating the movement of HSCs and facilitating their contact with stromal cells [119]. CXCL12, also known as SDF1, is a chemokine involved in cell homing. Deletion of SDF1 or its receptor CXCR4 leads to normal fetal heart hematopoiesis; however, there is a failure of bone marrow engraftment by hematopoietic cells [120,121]. Upregulation of CXCR4 in human hematopoietic progenitor cells results in enhanced engraftment in nude mice, whereas the use of CXCR4-neutralizing antibodies demonstrates an inhibitory effect on engraftment [122]. However, CXCR4 is not typically found in HSCs that are not actively dividing. This identifies the factors for successful HSC attachment and the molecules responsible for binding to osteoblasts. Osteoblasts express the adhesion molecules ALCAM and osteopontin, which may play a role in the interaction between HSCs and osteoblasts [123]. Furthermore, it is assumed that external factors such as BMPs, NOTCH ligands, and angiopoietins in bone marrow niches play a role in the interaction between HSCs and osteoblasts [94,101]. In some research, depletion of CXCL12 in osteoblasts resulted in the selective loss of B-lymphoid progenitors. Studies have shown that acute inflammation can inhibit osteoblastic bone formation, leading to T and B lymphopenia due to decreased production of interleukin-7 (IL-7). This suggests that osteoblasts may regulate common lymphoid progenitors by supplying IL-7 [124,125,126].

Myeloid lineage cells, including granulocytes and dendritic cells, also impact the HSC niche [127]. Granulocytes produce factors like G-CSF (granulocyte colony-stimulating factor), which promotes HSC mobilization from the bone marrow into the bloodstream. Dendritic cells contribute to HSC maintenance by modulating the expression of adhesion molecules and cytokines within the niche.

Due to the characteristics of HSCs, their self-renewal, multiple differentiation, and interactions with niche components, they can be used for the therapy of some blood-related diseases. Transplanting HSCs can restore patients HSC pools and also regenerate immune cell populations, which means that abnormal hematopoiesis has been replaced with normal hematopoiesis [128]. Hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, is utilized as a therapeutic approach for various blood-related diseases. HSCT offers a powerful therapeutic option by essentially resetting the hematopoietic and immune systems, allowing for the restoration of normal function and providing a potential cure for many serious conditions. It can be applied to patients as a therapeutic approach for various blood-related diseases, including malignant blood disorders such as lymphoma, multiple myeloma, and leukemia, as well as aplastic anemia and immunodeficiency disorders. It is especially considered in relapsed or refractory cases that do not respond to conventional chemotherapy or radiotherapy and in aggressive forms (e.g., diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma) [22,129,130,131].

Unlike solid organ transplantation, where the main goal is organ replacement, allogeneic hematopoietic cell transplantation for hematologic malignancies focuses on regulating the immune response against the underlying cancerous condition [128,132]. In leukemia, normal hematopoietic microenvironments are transformed into leukemic microenvironments by leukemic stem cells (LSCs). LSCs exhibit a high propensity for proliferation rather than differentiation into subset populations and possess strong resistance to drugs, resulting in poor prognosis and leukemia relapse [132,133,134,135,136]. For bone marrow transplantation, the most important thing is donor selection [137]. It is crucial to match the donors human leukocyte antigen (HLA) with the recipients as closely as possible to minimize the risk of graft rejection and graft-versus-host disease (GVHD). GVHD is a significant complication following HSCT, where donor immune cells attack the recipients tissues, leading to organ damage [138,139]. Immune checkpoint molecules such as TIGIT, PD-1, CTLA-4, and TIM-3 play pivotal roles in regulating immune responses in GVHD [140,141]. TIGIT and PD-1 inhibit T cell activation and effector functions [140,142,143,144,145,146], while CTLA-4 competes with CD28 for ligand binding, thereby inhibiting T cell activation [141,147]. TIM-3 regulates T cell exhaustion and tolerance [148,149]. Dysregulation of these markers can disrupt immune homeostasis, exacerbating GVHD pathology. Understanding the functions of immune checkpoint molecules is crucial for developing targeted therapies to mitigate GVHD severity post-HSCT. In a German study, after transplantation, the graft versus leukemia (GvL) effect in acute myeloid leukemia (AML) was found to significantly improve the 7-year relapse-free survival of patients with AML in first complete remission compared to conventional chemotherapy alone. This highlights its efficacy in disease control. However, transplantation at an advanced disease stage yields lower survival rates, emphasizing the importance of early consideration and referral for transplantation in eligible patients [150,151,152].

For successful transplantation, the recipients (patients) blood and immune system must initially be depleted by combinations of chemotherapy and radiotherapy [153]. Drugs used in conditioning therapy before bone marrow transplantation include cyclophosphamide, busulfan, melphalan, and fludarabine. These drugs induce apoptosis by interfering with DNA replication, transcription, and synthesis, thereby destroying the patients existing cells and suppressing the immune system. This helps prevent transplant rejection by adequately suppressing the immune system [154,155,156,157]. If this pre-HCT conditioning is performed well, donor HSCs can home to and engraft the recipients bone marrow, thereby reconstituting all the blood cell lineages. Immune recovery after HSCT occurs in phases, with innate immune cells and platelets generally recovering within weeks after HSCT; fully complete reconstitution of adaptive immunity may extend over months to even years (Figure 3) [158,159,160,161].

Dynamics of immune reconstitution and associated risks in recipients bone marrow following hematopoietic stem cell transplantation. In the first few weeks after transplantation, innate immune cells recover swiftly. Common infections during this phase include bacterial and Candida infections due to the early deficiency in adaptive immune cells. Meanwhile, adaptive immune function, including T cells and B cells, exhibits prolonged deficiencies and gradually recovers, taking over 2 years to fully restore. Viral infections and those caused by non-Candidal molds become more common during this phase. Various clinical factors, including conditioning regimens, donor sources, and post-transplant events such as graft-versus-host disease (GVHD) and immunosuppression, exert influence over the immune reconstitution process, thereby modulating the associated infectious risks.

During this process, various cells within the bone marrow serve as niche components for donor HSCs. The BM niche provides the microenvironment necessary for hematopoietic stem cell (HSC) maintenance, differentiation, and proliferation. Endothelial cells play a significant role in the regulation of various processes, including the quiescence, proliferation, and mobilization of HSCs. It is anticipated that ECs will aid in the hematopoietic recovery of donor HSCs following transplantation. Although ECs are often damaged during conditioning for HCT, when transplanted alongside HSCs, they have been shown to confer beneficial effects in terms of HSC engraftment, reconstitution, and survival post-irradiation [162,163,164]. MSCs, as a rare component of the bone marrow niche, play a crucial role in regulating HSC homeostasis through the production of key soluble factors. Different subsets of MSCs have distinct impacts on HSC behavior, supporting either quiescent or proliferative states. Despite surviving conditioning regimens, MSCs may accumulate damage, potentially affecting their functionality. In clinical contexts, MSCs have shown promise in enhancing HSC engraftment and treating complications like steroid-resistant aGvHD, although further research is needed to elucidate their precise mechanisms of action [165,166,167].

Hematopoietic stem cells (HSCs) possess the remarkable ability to generate all lower cells of the hematopoietic hierarchy and regulate the entire process of hematopoiesis through self-renewal and proliferation. The uninterrupted generation of new blood cells is indispensable for the survival of organisms, underscoring the critical importance of maintaining the normal function of HSCs throughout life. Normal hematopoiesis involves maintaining a good balance between activated HSCs that produce blood and quiescent HSCs that do not function. However, when HSCs are damaged due to various factors, such as aging, their function is compromised, leading to aberrant hematopoiesis and potentially giving rise to hematological diseases, including aplastic anemia, myelodysplastic syndromes, and leukemia.

Aging affects the overall functioning of an organism, and blood production is also strongly affected. Various research results have revealed that aging affects the function of HSCs, causing their parts to change abnormally. Functional and genomic analysis has been conducted through mouse experiments, and the phenotype in elderly people is similar. Aging eventually causes diseases such as immune disorders, lymphoma, and leukemia, and the prognosis is worse for elderly patients whose hematopoiesis and immune systems have already collapsed.

The niche of HSCs interacts with cells in various aspects to regulate their functions. Osteoblast cells in the bone-adjacent area of the bone marrow lumen play a crucial role in regulating the state of HSCs through various mechanisms. Osteoblasts express Ang1 and OPN, which bind to specific receptors expressed on HSCs, causing them to remain stationary in a specific area. This interaction helps maintain the quiescent state of HSCs and regulates their retention within the bone marrow niche.

Vascular tissue refers to vascular components including vascular endothelial cells, pericytes, and SMCs, as well as stromal cells, which are supporting cells around them. Endothelial cells (ECs) and pericytes are classified according to the location of blood vessels (sinusoids or arterioles), and they both regulate HSCs by secreting various chemokines, including CXCL12 and SCF. These soluble factors perform different functions depending on their site of secretion, either promoting the quiescence or activation of HSCs.

HSC transplantation is gaining attention as a treatment for diseases stemming from HSC damage, particularly leukemia. Just as HSCs interact with niche components to sustain ongoing hematopoiesis, hematopoiesis can be restored by transplanting HSCs from a healthy donor into patients with HSC or niche defects. However, due to the limited understanding of the niche in the context of bone marrow transplantation, ongoing research is crucial to address issues like GVHD.

Writingoriginal draft preparation, M.K.; conceptualization, B.S.K., S.Y., S.-O.O. and D.L.; funding acquisition, D.L. All authors have read and agreed to the published version of the manuscript.

The authors declare no conflicts of interest.

This research was supported by grants from the Korean Cell-Based Artificial Blood Project funded by the Korean government (The Ministry of Science and ICT; the Ministry of Trade, Industry, and Energy; the Ministry of Health & Welfare; the Ministry of Food and Drug Safety) [grant no. HX23C1692], and grants from the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education and the Ministry of Health & Welfare [grant nos. 2022R1A5A2027161, RS-2023-00223764, and RS-2024-00333287].

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November 15th, 2024

Bone Marrow Transplant Program – Overview – Mayo Clinic

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Bone marrow transplant patient care

You will be cared for by a team of experts in bone marrow transplant.

Mayo Clinic's bone marrow (stem cell) transplant team is recognized internationally for its expertise in comprehensive specialty treatment for people with blood and bone marrow diseases. Mayo Clinic is one of the largest providers of bone marrow transplants in the United States. It has performed more than 10,000 stem cell transplants at its campuses in Arizona, Florida and Minnesota.

At Mayo Clinic, bone marrow transplant experts help adults and children with leukemia and other blood, plasma and bone marrow diseases. Your doctors will talk with you about all treatment options appropriate for you, including experimental treatments, and deliver care tailored to your needs.

Mayo Clinic bone marrow transplant experts are involved in patient care and research in the Mayo Clinic Comprehensive Cancer Center, designated by the National Cancer Institute as a comprehensive cancer center. The Mayo Clinic Comprehensive Cancer Center ranks in the top tier of cancer centers in the United States for Cancer research, treatment and education. Mayo Clinic Comprehensive Cancer Center is also a member of the National Comprehensive Cancer Network.

Your bone marrow transplant team collaborates to ensure you get exactly the care you need.

Mayo Clinic's experts focus on your needs, bringing to your situation the strength of their:

Experience. Specialists in bone marrow transplant and hematology at Mayo Clinic have extensive experience helping people with all types of diseases, including very rare ones. For example, they are leaders in the use of blood stem cell transplants to treat amyloidosis.

Each year, more than 30,000 people with blood diseases are treated at Mayo Clinic, and more than 700 of them undergo bone marrow transplants. This experience means your doctors are prepared with the knowledge and resources to provide exactly the care you need.

Innovative research. Mayo Clinic researchers make bone marrow transplants safer and improve the lives of people who need them. Their innovative treatments harness the body's immune system, make use of new stem cell technologies and prevent complications such as graft versus host disease.

Mayo Clinic bone marrow transplant physicians and hematologists work with other hospitals in the United States and internationally to conduct clinical trials. The close connection between clinical care and research at Mayo Clinic makes it possible for eligible patients to enroll in clinical trials, where they may receive new treatments.

Mayo Clinic bone marrow transplant experts and hematologists are also involved in patient care and research in the Mayo Clinic Comprehensive Cancer Center. This center ranks in the top tier of cancer centers in the United States.

At Mayo Clinic's campus in Minnesota, children and adolescents with blood disorders receive care through the Children's Center. Children needing hospitalization receive care at Mayo Eugenio Litta Children's Hospital.

At Mayo Clinic's campus in Arizona, doctors trained in blood diseases and cancer (hematologists and oncologists) partner with Phoenix Children's Hospital to treat children who may need bone marrow transplants. Together the two hospitals oversee a single bone marrow transplant program for children.

At Mayo Clinic's campus in Florida, hematologists and oncologists partner with Nemours Children's Specialty Care and Wolfson Children's Hospital to treat children who may need bone marrow transplants.

Mayo Clinic's Bone Marrow Transplant Program provides consultations, evaluations and treatment for patients who would potentially benefit from a bone marrow transplant.

Mayo Clinic bone marrow transplant specialists work with a multidisciplinary team to determine the most appropriate treatment for you. They have expertise in many areas of bone marrow transplant, including those listed below. Not all services are available at each of Mayo Clinic's three campuses in Arizona, Florida and Minnesota. Please confirm when you call to request an appointment.

Mayo Clinic in Rochester, Minnesota, Mayo Clinic in Jacksonville, Florida, and Mayo Clinic in Phoenix/Scottsdale, Arizona, are ranked among the Best Hospitals for cancer by U.S. News & World Report.

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Bone Marrow Donors Can Be Hard to Find. One Company Is Turning to Cadavers – WIRED

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More stem cells for sickle cell gene therapy readied with motixafortide – Sickle Cell Disease News

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Skull bone marrow expands throughout life and remains healthy during aging, researchers discover – Medical Xpress

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Skull bone marrow expands throughout life and remains healthy during aging, researchers discover Medical Xpress

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Adult skull bone marrow is an expanding and resilient haematopoietic reservoir – Nature.com

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Stem cells grown in space show super powers but theres a catch – Study Finds

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Cutting-edge stem cell therapy proves safe, but will it ever be … – AAAS

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It's official: The first use of induced pluripotent stem (iPS) cells in a human has proved safe, if not clearly effective. Japanese researchers reported in this week's issue of The New England Journal of Medicine (NEJM) that using the cells to replace eye tissue damaged by age-related macular degeneration (AMD) did not improve a patient's ...

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Science Is Finding Ways to Regenerate Your Heart – The Wall Street Journal

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Induced pluripotent stem cell – Wikipedia

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A scheme of the generation of induced pluripotent stem (IPS) cells. (1) Isolate and culture donor cells. (2) Transduce stem cell-associated genes into the cells by viral vectors. Red cells indicate the cells expressing the exogenous genes. (3) Harvest and culture the cells according to ES cell culture, using mitotically inactivated feeder cells (lightgray). (4) A small subset of the transfected cells become iPS cells and generate ES-like colonies.

iPSCs are typically derived by introducing products of specific sets of pluripotency-associated genes, or "reprogramming factors", into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and cMyc. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.[11] It is also clear that pro-mitotic factors such as C-MYC/L-MYC or repression of cell cycle checkpoints, such as p53, are conduits to creating a compliant cellular state for iPSC reprogramming.[12]

iPSC derivation is typically a slow and inefficient process, taking onetwo weeks for mouse cells and threefour weeks for human cells, with efficiencies around 0.010.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University, Japan, in 2006.[1] They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

In June 2007, three separate research groups, including that of Yamanaka's, a Harvard/University of California, Los Angeles collaboration, and a group at MIT, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells.

These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs.[13][14][15][16]

Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, Oct4, Sox2, Klf4, and cMyc, using a retroviral system,[17] while Thomson and colleagues used a different set of factors, Oct4, Sox2, Nanog, and Lin28, using a lentiviral system.[18]

Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible.[19][20] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck.[21][22] In 2010, iPSCs were derived from peripheral blood cells,[23][24] and in 2012, iPSCs were made from renal epithelial cells in the urine.[25]

Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[19][20] time it takes to expand the population of starting cells,[19] and the ability to differentiate into a given cell type.[26]

[citation needed]

The generation of induced pluripotent cells is crucially dependent on the transcription factors used for the induction.

Oct-3/4 and certain products of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table on the right summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small molecules that can mimic the effects of transcription factors. These compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanaka's traditional transcription factor method).[42] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[43] Deng et al. of Beijing University reported in July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[44][45]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the mesenchymal-epithelial transition (MET) process in which fibroblasts are pushed to a stem-cell like state, Ding's group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks.[46][47]

In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[48] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

Another key strategy for avoiding problems such as tumorgenesis and low throughput has been to use alternate forms of vectors: adenoviruses, plasmids, and naked DNA or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[43] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[49] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[35] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the PiggyBac Transposon System. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis.[citation needed]

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[50]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[51] On 4 June 2014, the lead author, Obokata agreed to retract both the papers[52] after she was found to have committed 'research misconduct' as concluded in an investigation by RIKEN on 1 April 2014.[53]

MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential.[54] Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed.[54] ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc.[55] MicroRNAs can also block expression of repressors of Yamanaka's four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.[54]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells.[58] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound.[67]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[68][69][70] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy subjects, providing insight into the pathophysiology of the disease.[71][72] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of diseases. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[73] Furthermore, combining hiPSC technology and small molecule or genetically encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening.[74][75][76][77][78]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human 'liver buds' (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocyte (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the 'liver' quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[79][80]

In 2021, a switchable Yamanaka factors-reprogramming-based approach for regeneration of damaged heart without tumor-formation was demonstrated in mice and was successful if the intervention was carried out immediately before or after a heart attack.[81]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[82][83]

Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.[84]

Beating cardiac muscle cells, iPSC-derived cardiomyocytes, can be mass-produced using chemically defined differentiation protocols.[85][86] These protocols typically modulate the same developmental signaling pathways required for heart development.[87] These iPSC-cardiomyocytes can recapitulate genetic arrhythmias and cardiac drug responses, since they exhibit the same genetic background as the patient from which they were derived.[88][89][90][91]

In June 2014, Takara Bio received technology transfer from iHeart Japan, a venture company from Kyoto University's iPS Cell Research Institute, to make it possible to exclusively use technologies and patents that induce differentiation of iPS cells into cardiomyocytes in Asia. The company announced the idea of selling cardiomyocytes to pharmaceutical companies and universities to help develop new drugs for heart disease.[92]

On March 9, 2018, the Specified Regenerative Medicine Committee of Osaka University officially approved the world's first clinical research plan to transplant a "myocardial sheet" made from iPS cells into the heart of patients with severe heart failure. Osaka University announced that it had filed an application with the Ministry of Health, Labor and Welfare on the same day.

On May 16, 2018, the clinical research plan was approved by the Ministry of Health, Labor and Welfare's expert group with a condition.[93][94]

In October 2019, a group at Okayama University developed a model of ischemic heart disease using cardiomyocytes differentiated from iPS cells.[95]

Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.[96]

The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 at the Riken Center for Developmental Biology in Kobe. However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015.[97] More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations).[98] iPSCs derived from skin cells from six patients with wet age-related macular degeneration were reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into the affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring were to last one to three years.[99][100]

In March 2017, a team led by Masayo Takahashi completed the first successful transplant of iPS-derived retinal cells from a donor into the eye of a person with advanced macular degeneration.[101] However it was reported that they are now having complications.[102] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and that it eliminates the need to use embryonic stem cells. However, these iPSCs were derived from another person.[100]

New clinical trials involving iPSCs are now ongoing not only in Japan, but also in the US and Europe.[103] Research in 2021 on the trial registry Clinicaltrials.gov identified 129 trial listings mentioning iPSCs, but most were non-interventional.[104]

To make iPSC-based regenerative medicine technologies available to more patients, it is necessary to create universal iPSCs that can be transplanted independently of haplotypes of HLA. The current strategy for the creation of universal iPSCs has two main goals: to remove HLA expression and to prevent NK cells attacks due to deletion of HLA. Deletion of the B2M and CIITA genes using the CRISPR/Cas9 system has been reported to suppress the expression of HLA class I and class II, respectively. To avoid NK cell attacks. transduction of ligands inhibiting NK-cells, such as HLA-E and CD47 has been used.[105] HLA-C is left unchanged, since the 12 common HLA-C alleles are enough to cover 95% of the world's population.[105]

A multipotent mesenchymal stem cell, when induced into pluripotence, holds great promise to slow or reverse aging phenotypes. Such anti-aging properties were demonstrated in early clinical trials in 2017.[106] In 2020, Stanford University researchers concluded after studying elderly mice that old human cells when subjected to the Yamanaka factors, might rejuvenate and become nearly indistinguishable from their younger counterparts.[107]

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Advancing heart stem cell therapy – UHN Foundation

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