Disease-specific Treatment
Clinical Trial Data
Therapeutic Indications of MSCs Across 352 Registered Clinical Trials
Indications Being Addressed using MSCs in Clinical Trials. Data for 352 registered clinical trials.
Citation// Stem Cell Therapies in Clinical Trials: Progress and Challenges. Trounson, Alan et al. Cell Stem Cell , Volume 17 , Issue 1 , 11 – 22
Clinical Indications: Longevity Medicine
Pluripotent stem cells possess a remarkable capacity for self-renewal and the potential to differentiate into a diverse array of specialized cell types. However, a growing body of evidence indicates that the chronological aging process compromises stem cell fitness. Upon undergoing senescence, stem cells exhibit a decline in their regenerative potency and a disrupted lineage-specific differentiation potential.
Consequently, mounting evidence suggests that age-driven attrition of stem cell function plays a pivotal role in the pathophysiology of various age-related disorders. Elucidating the mechanisms governing stem cell senescence is therefore crucial—not only to unraveling the pathophysiological foundations of these conditions, but also to pioneering effective, next-generation stem cell-based therapeutics to combat age-related diseases.
This review article focuses on the fundamental pathways underlying age-related stem cell dysfunction across various disorders. It further explores key mechanistic concepts driving this cellular decline. Finally, we provide a concise overview of emerging, next-generation therapeutic strategies aimed at reversing or mitigating age-associated stem cell deficiencies.
Citation// World J Exp Med. 2017 Feb 20; 7(1): 1–10.Effect of aging on stem cells. Abu Shufian Ishtiaq Ahmed,et al
Clinical Indications: Hepatic and Diabetic Disorders
Regenerative medicine has actively transitioned into clinical programs, leveraging stem and progenitor cell therapies to repair damaged organs. Here, we briefly review human biliary tree stem cells (hBTSCs) niche within the biliary tract—an anatomical framework bridging the liver and pancreas, which fundamentally share a common endodermal stem cell lineage.
These populations serve as the upstream precursors to hepatic stem/progenitor cells within the canals of Hering, as well as progenitor cells residing in the pancreatic ductal glands. They drive cellular maturation along two distinct axes: a radial axis within the bile duct wall, and a proximal-distal axis that originates in the duodenum and culminates in mature functional cells within the liver or pancreas. Concurrently, clinical trials evaluating the therapeutic impact of these stem cells—specifically fetal liver-derived hepatic stem/progenitor cells—transplanted via the hepatic artery in patients with diverse liver diseases have been actively conducted for many years.
Immunosuppression was not required. All control subjects receiving the standard of care either succumbed to the disease or experienced a decline in liver function within one year. Conversely, subjects transplanted with 100 to 150 million hepatic stem/progenitor cells demonstrated significant improvements in both liver function and long-term survival spanning several years. While larger multi-center trials are ongoing, the foundational safety and efficacy profiles of this transplantation approach continue to be progressively validated.
While stem cell therapeutics for diabetes utilizing hBTSCs remain under active investigation, clinical translation is expected to accelerate upon the conclusion of ongoing preclinical trials. Concurrently, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are already being deployed in patients with chronic liver diseases or diabetes. Rather than relying on direct differentiation into mature parenchymal or pancreatic islet cells—a lineage-restricted pathway known to be relatively inefficient—MSCs primarily exert their therapeutic efficacy via the paracrine secretion of trophic and immunomodulatory factors. Conversely, the clinical benefits of HSCs are predominantly driven by the targeted modulation of systemic immune mechanisms.
Stem Cells. 2013 Oct;31(10):2047-60. doi: 10.1002/stem.1457. Concise review: clinical programs of stem cell therapies for liver and pancreas.Lanzoni G1, Oikawa T
Diabetes
QinanWu, Bing Chen, and Ziwen Liang,
Mesenchymal Stem Cells as a Prospective Therapy for the Diabetic Foot
Stem Cells International Volume 2016, Article ID 4612167, 18 pages https://onlinelibrary.wiley.com/doi/10.1155/2016/4612167
Mechanistic Pathways of MSC Transplantation for Diabetic PAD
Stem cell transplantation mediates therapeutic recovery through two distinct mechanistic pathways: first, via the targeted secretion of potent angiogenic factors and cytoprotective cytokines (paracrine signaling); and second, through the direct engraftment and differentiation of stem cells into functional tissue architecture. By significantly enhancing the localized secretion and molecular expression of these angiogenic and cytokine profiles, stem cells drive the reconstruction of the microcirculatory network, effectively restoring regional blood flow and revitalizing pancreatic islet β-cell function—ultimately leading to the systemic resolution of diabetic PAD. Concurrently, stem cells possess the capacity to differentiate directly into functional endothelial cells, thereby reversing endothelial dysfunction from its root cause. Emerging evidence indicates that these synergistic regenerative outcomes are fundamentally orchestrated by specific microRNAs (miRNAs) and mesenchymal stem cell-derived exosomes (MEXs).
Mechanistic Pathways of MSC Transplantation for Diabetic Wound Healing
MSC transplantation accelerates diabetic wound healing through three synergistic mechanistic pathways: first, via robust angiogenesis and the paracrine secretion of essential growth factors and cytokines; second, through the comprehensive orchestration of the immune system; and third, via the direct engraftment and differentiation of stem cells into functional tissue architecture. By significantly enhancing the localized secretion and molecular expression of these angiogenic and cytokine profiles, MSCs drive microvascular remodeling, directly contributing to the systemic improvement of diabetic PAD and metabolic homeostasis. Simultaneously, MSCs exert potent immunomodulatory effects by precisely regulating the activities of T cells, natural killer (NK) cells, macrophages, and dendritic cells—thereby suppressing opportunistic infections and resolving chronic, non-healing inflammatory responses. Furthermore, MSCs possess the targeted homing capacity to differentiate into specific lineages within the damaged target tissue, achieving structural and functional repair from its root cause. Emerging evidence indicates that these multifaceted regenerative cascades are fundamentally orchestrated by specific microRNAs (miRNAs) and mesenchymal stem cell-derived exosomes (MEXs).
Mechanistic Pathways of MSC Transplantation for Diabetic Neuropathy
The therapeutic recovery mediated by stem cell transplantation operates through two distinct mechanistic pathways: first, via the targeted secretion of potent angiogenic factors, immunomodulatory cytokines, and neurotrophic factors; and second, through the direct engraftment and differentiation of stem cells into functional tissue architecture. By significantly enhancing the localized secretion and molecular expression of these angiogenic and cytokine profiles, stem cells drive microvascular remodeling—directly contributing to the systemic resolution of diabetic PAD and metabolic homeostasis, which concurrently halts the progression of diabetic neuropathy. Simultaneously, the specialized neurotrophic factors actively reverse nerve fiber dysfunction and accelerate nerve conduction velocity (NCV). Furthermore, stem cells possess the targeted homing capacity to differentiate directly into lineage-specific cells within damaged target tissues, achieving structural and functional repair from its root cause.
Renal Failure & Kidney Therapeutics
Alfonso Eirin and Lilach O Lerman* Mesenchymal stem cell treatment for chronic renal failure,
Stem Cell Research & Therapy 2014, 5:83 http://stemcellres.com/content/5/4/83
In animals receiving mesenchymal stem cell therapy, renal artery stenosis, microvascular loss, and interstitial fibrosis were significantly attenuated.
Top: 3D micro-computed tomography (micro-CT) imaging of a kidney segment, capturing the rescued microvascular architecture in a pig model of atherosclerotic renal artery stenosis. The animal underwent percutaneous transcatheter renal angioplasty (PTRA) four weeks following a prior intra-adrenal infusion of adipose tissue-derived mesenchymal stem cells (MSCs).
Bottom: Renal trichrome staining (×40, blue) showing reduced MSC fibrosis in porcine with ARAS + PTRA.
Clinical Efficacy: MSC Applications in Diabetic Disorders
Stem cell transplantation represents a demonstrably safe and effective therapeutic modality for patients with diabetes mellitus (DM). Within this integrated series of clinical trials for Type 1 Diabetes (T1DM), the most favorable therapeutic outcomes were achieved utilizing CD34+ hematopoietic stem cell (HSC) therapy; conversely, the least favorable clinical responses were observed in cohorts receiving human umbilical cord blood (HUCB) transplantation. Crucially, the presence of diabetic ketoacidosis (DKA) significantly compromises the overall efficacy of the cellular intervention.
Line graphs showing changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months after stem cell therapy in T1DM patients. All data are expressed as mean ± SEM. **** P < 0.0001
The outcome for stem cell therapy for T2DM
Stem cell therapy for type 2 DM.
A-D) Bar graphs showing baseline and 12-month changes in C-peptide and HbA1c levels after administration of different types of stem cells. UC-MSC and PD-MSC were administered intravenously (n = 22 and n = 10, respectively), while UCB and BM-MNC were administered intrapancreatally (n = 3 and n = 107, respectively).
E-F）Line graphs showing changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months after stem cell therapy in T2D patients.
Citation// PLoS One. 2016 Apr 13;11(4):e0151938. Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis. El-Badawy A, El-Badri N.
Trichology & Hair Regeneration
Nat Commun. 2012 Apr 17;3:784. doi: 10.1038/ncomms1784.
Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches.
Toyoshima KE1, Asakawa K, Ishibashi N, Toki H, Ogawa M, Hasegawa T, Irié T, Tachikawa T, Sato A, Takeda A, Tsuji T.
Overview: Organ replacement regenerative medicine is poised to enable the complete restoration of organs damaged by disease, injury, or aging in the foreseeable future. Here, we demonstrate fully functional organ regeneration via the intradermal transplantation of bioengineered hair follicle germs. These engineered germs are meticulously reconstituted using embryonic skin-derived epithelial cells and adult stem cell niche-derived mesenchymal cells, respectively. The bioengineered hair follicles develop proper anatomical structures and establish functional connections with surrounding host tissues, including the epidermis, arrector pili muscles, and nerve fibers. Furthermore, these bioengineered follicles exhibit a successfully restored hair cycle and robust hair shaft formation, driven by the structural reorganization of hair follicle stem cells and their microenvironmental niches. Consecutively, this study elucidates the profound therapeutic potential of adult tissue-derived hair follicle stem cells for bioengineered organ replacement therapies.
(a) Schematic representation of the fabrication and transplantation methodology for bioengineered hair follicle germs.
(b) Phase-contrast microscopy of embryonic mouse dorsal skin, intact tissue, dissociated single cells, and a bioengineered hair follicle germ reconstructed via the organ germ method utilizing a nylon thread (arrowhead). (Scale bar: 200 μm)
(c) Histological analysis of vibrissae isolated from adult mice. Macroscopic morphology and H&E-stained vibrissae are presented in the two leftmost panels. The red dashed lines in both the macromorphological image (left) and H&E staining (right) delineate the interface between the bulge and sub-bulge (SB) regions. The boxed area in the left panel is visualized via H&E staining to highlight the bulge, while the SB region is displayed at higher magnification in the right panel. The bulge region was characterized by immunohistochemistry using anti-CD49f (red, left) and anti-CD34 (red, center) antibodies, counterstained with Hoechst 33258 (blue). The black dashed line in the high-magnification H&E image indicates the epithelial-mesenchymal interface of the hair follicle. IF, infundibulum; RW, ring wulst; HS, hair shaft. (Scale bar: 100 μm) (d) Histological and alkaline phosphatase (ALP) analysis of the vibrissa bulb region and primary dermal papilla (DP) cell cultures. Hair bulbs (two left panels) and cultured DP cells (two right panels) were evaluated via enzymatic ALP staining. The red dotted line delineates Auber's line. (Scale bar: 100 μm)
(e) Longitudinal sections of bioengineered hair during the emergence and growth phases, facilitated by an interepithelial tissue-connecting plastic device (with guide). Conversely, control transplants without the guide resulted in intradermal cyst formation by day 14. Sequential H&E staining (top) and fluorescence microscopy (bottom) track the bioengineered hair follicles at 0, 3, and 14 days post-transplantation. (Scale bar: 100 μm)
(f) Macromorphological observation of hair growth during the developmental and maturation phases of bioengineered hair follicles grafted onto the chest (top) and spleen (bottom) host sites. Images sequentially demonstrate immediate post-transplantation status on day 0 (left), wound healing by day 3 (center), and robust hair shaft emergence and elongation on days 14 and 37 (right). (Scale bar: 1.0 mm)
(a) Histological and immunohistochemical analysis of bioengineered pelage (top) and vibrissa (center) hair follicles. The boxed areas in the low-magnification H&E panels are displayed at higher magnification in the corresponding right panels. Arrows indicate sebaceous glands. (Scale bar: 100 μm) The hair bulbs of bioengineered follicles were characterized via immunohistochemistry using anti-versican (bottom left) and $\alpha$-SMA (arrowhead, bottom right) antibodies, and evaluated via enzymatic ALP staining (bottom center). (Scale bar: 50 μm)
(b) Bioengineered human hair generated via the transplantation of bioengineered hair follicle germs, meticulously reconstituted using bulge-derived epithelial cells and intact dermal papilla (DP) cells isolated from human scalp hair follicles. On day 21 post-transplantation, the bioengineered human hair was captured via stereomicroscopy and further analyzed through H&E staining. The species-specific origin of the bioengineered hair follicles was validated based on nuclear morphological characteristics (right panel). The boxed area in the inset is displayed at higher magnification. (Scale bars: 500 μm (microscopy), 100 μm (H&E), and 20 μm (nuclear staining))
(c) High-density intradermal transplantation of bioengineered hair follicle germs. A total of 28 independent bioengineered hair follicle germs were grafted into the host skin of mice, demonstrating robust, high-density hair growth by day 21 post-transplantation. (Scale bar: 5 mm)
The bioengineered pelage and vibrissa hair follicles established functional connections with surrounding host- or donor-derived tissues, including nerve fibers, arrector pili muscles, and striated muscles. Specifically, the fully engineered hair follicles successfully integrated with smooth muscle architecture as a direct result of the regeneration of the bulge region expressing Nephronectin (NPNT), mimicking the anatomical features of natural hair follicles. Conversely, in the bioengineered hair follicles that formed cysts (without guide), neither NPNT expression nor smooth muscle integration was detected within the disorganized bulge regions.
Citation: Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Koh-ei Toyoshima, Kyosuke Asakawa, Naoko Ishibashi, Hiroshi Toki, Miho Ogawa, Tomoko Hasegawa, Tarou Irié, Tetsuhiko Tachikawa, Akio Sato, Akira Takeda & Takashi Tsuji. Nature Communications 3, Article number: 784 (2012)
doi:10.1038/ncomms1784
Parkinson's Disease & Neuro-Regeneration
A schematic diagram illustrating the induction, differentiation, and application of stem cells currently available in PD research and treatment.
The stem cells mentioned above can be divided into four categories: ESCs, NSCs, MSCs, and iPSCs, and they exhibit a gradually decreasing pluripotency.
(1) Embryonic stem cells (ESCs), primarily derived from the inner cell mass (ICM) of the blastocyst, possess the inherent capacity to differentiate into all three primary germ layers—endoderm, mesoderm, and ectoderm—under physiological conditions. Furthermore, given specific microenvironmental cues, ESCs can be successfully induced to lineage-specify into neural stem cells (NSCs) and mesenchymal stem cells (MSCs).
(2) Neural stem cells (NSCs)—whether isolated directly from specialized neurogenic niches within the brain or induced via direct reprogramming of fibroblasts—possess the multi-lineage capacity to differentiate into functional neurons and virtually all macroglial cell types of the nervous system.
(3) Mesenchymal stem cells (MSCs) originate primarily from mesodermal tissues and possess the multilineage plasticity to differentiate into virtually all cell types of mesodermal lineages. Strikingly, crossing conventional germ-layer boundaries, MSCs can also be successfully transdifferentiated into functional dopaminergic (DA) neurons when exposed to specific combinations of optimized induction protocols.
(4) Induced pluripotent stem cells (iPSCs)—which are successfully reprogrammed from adult human somatic cells (such as fibroblasts) via the ectopic introduction of the OSKM pluripotency factors (Oct3/4, Sox2, Klf4, and c-Myc)—represent an exceptionally promising cell source characterized by robust multi-lineage differentiation potential. Adhering strictly to current Good Manufacturing Practice (cGMP) standards, these stem cells and their terminally differentiated progeny can be meticulously sorted, purified, and scale-expanded. This high-purity cellular output is critically optimized for downstream applications, including the establishment of pathophysiological disease models, high-throughput drug screening, and the clinical implementation of Cellular Regenerative Therapy (CRT). For instance, the specific modalities of ESCs, MSCs, NSCs, and functional DA neurons are utilized in the following paradigms:
(i) Pathophysiological PD model generation (ii) High-throughput screening for potential therapeutics (iii) Clinical implementation of CRT for PD
Front. Aging Neurosci., 31 May 2016. A Compendium of Preparation and Application of Stem Cells in Parkinson’s Disease: Current Status and Future Prospects. Yan Shen, Jinsha Huang
