Treatment by disease

Indications indicated with MSCs in clinical trials. Data from 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

Pluripotent stem cells have remarkable self-renewal capacity and can differentiate into multiple diverse cells. There is growing evidence that the aging process can adversely affect stem cells. As stem cells age, their regenerative capacity declines and their ability to differentiate into various cell types is altered. Therefore, it has been suggested that aging-induced decline in stem cell function may play an important role in the pathophysiology of various age-related diseases. Understanding the role of the aging process in stem cell function is important not only for understanding the pathophysiology of aging-related diseases, but also for developing effective stem cell-based therapeutics to treat aging-related diseases in the future. . This review article focuses on the underlying stem cell dysfunction associated with various aging-related diseases. Next, we discuss some concepts regarding the possible mechanisms responsible for senescence-associated stem cell dysfunction. We also briefly discuss current potential therapeutics for senescence-related stem cell defects that are under development.
Citation// World J Exp Med. 2017 Feb 20; 7(1): 1–10.Effect of aging on stem cells. Abu Shufian Ishtiaq Ahmed,et al

Regenerative medicine is moving into clinical programs using stem/progenitor cell therapy for the repair of damaged organs. We briefly describe biliary stem cells (hBTSCs) located in the liver and pancreas, an organ that shares an endodermal stem cell population, the biliary stem. They are precursors of hepatic stem/progenitor cells in the Hering ducts and progenitor cells of the pancreatic glands. They give rise to a mature lineage along a radial axis within the bile duct wall and a proximal-distal axis that originates in the duodenum and terminates in mature cells in the liver or pancreas. Clinical trials evaluating the effects of stem cells (hepatic stem/progenitor cells derived from fetal liver) transplanted into the hepatic artery of patients with various liver diseases have been conducted for many years. No immunosuppression was required. All control subjects given a given criterion died or had compromised liver function within 1 year. Subjects transplanted with 100-150 million liver stem/progenitor cells showed improved liver function and survival over several years. Assessment of safety and efficacy of transplantation is still developing. Stem cell therapy for diabetes using hBTSCs is still being investigated, but likely after ongoing preclinical trials. In addition, mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC) are used in patients with chronic liver disease or diabetes. MSCs exert their effects via paracrine trophic and immunomodulatory factors, with limited inefficient lineage restriction to mature parenchymal cells or pancreatic islet cells. The effects of HSC are primarily due to modulation of the immune system.

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

Figure 1: Mechanism of effect of MSC transplantation on diabetic PAD. Mechanisms of restorative effects mediated by stem cell transplantation from two pathways: one is the secretion of angiogenic factors and cytokines and the other is the engraftment and differentiation of cells into tissue constituents. Stem cells can specifically improve the local secretion and expression of angiogenic factors and cytokines, contributing to remodeling the microcirculatory system and improving blood flow and islet β-cell function, leading to improvement in diabetic PAD. . Stem cells can also differentiate into endothelial cells to achieve restoration of endothelial cell dysfunction. These effects may be related to miRNAs and MEX.

Figure 2: Mechanism of effect of MSC transplantation on diabetic wounds. Diabetic wound repair by MSC transplantation from three pathways: the first is angiogenesis and secretion of factors and cytokines, the second is regulation of the immune system, and the third is engraftment and differentiation of cells into tissue constituents. be. Stem cells can specifically improve local secretion and expression of angiogenic factors and cytokines that contribute to the improvement of diabetic PAD and diabetes. Stem cells can also modulate the activity of T cells, natural killer cells, macrophages, and dendritic cells, and can inhibit infection and inflammatory responses. In addition, MSCs can differentiate into target tissues to accomplish repair. These effects may be related to miRNAs and MEX.

Figure 3: Mechanism of effect of MSC transplantation on diabetic neuropathy. The mechanisms of restorative effects mediated by stem cell transplantation arise from two pathways: one is the secretion of angiogenic factors, cytokines and neurotrophic factors and the other is the engraftment and differentiation of cells into tissue constituents. Stem cells can specifically improve local secretion and expression of angiogenic factors and cytokines, contributing to improvement of diabetic PAD and diabetes itself, leading to improvement of diabetic neuropathy. Neurotrophic factors can also improve nerve fiber dysfunction and nerve conduction. In addition, stem cells can differentiate into target tissues to accomplish repair.

Stenosis-renal microvascular loss and fibrosis were reduced in animals receiving mesenchymal stem cell therapy. Top: Three-dimensional representative microcomputed tomography of a kidney segment capturing improved microvasculature in a pig with atherosclerotic renal artery stenosis undergoing percutaneous transluminal renal angioplasty (PTRA). Imaging, intra-adrenal infusion of adipose tissue-derived mesenchymal stem cells (MSCs) was performed as early as 4 weeks. Bottom: Representative renal trichrome staining showing reduced MSC fibrosis in ARAS + PTRA + pigs (x40, blue)

Stem cell transplantation can be a safe and effective treatment for patients with DM. In this series of trials, the best outcome was achieved with D34 + HSC therapy for T1DM, whereas the worst outcome was observed with HUCB for T1DM. Diabetic ketoacidosis interferes with therapeutic efficacy.

Line graph 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 graph showing changes in C-peptide and HbA1c levels at baseline and after 12 months after administration of different types of stem cells. UC-MSCs and PD-MSCs were injected intravenously (n = 22 and n = 10, respectively), while UCB and BM-MNC were injected intrapancreatically (n = 3 and n = 107) (EF) Stem cells in T2D Line graph showing changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months after treatment.

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.

overview
Organ replacement regenerative medicine is said to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional organ regeneration via intradermal implantation of bioengineered bone and spore germination. The blastoderm and ovule are reconstituted with embryonic skin-derived cells and adult stem cell region-derived cells, respectively. Bioengineered hair follicles develop the correct structures and form appropriate connections with surrounding host tissues such as epidermis, hindlimb muscles and nerve fibers. Bioengineered hair follicles also exhibit restored hair cycle and hair follicle formation through reorganization of follicle stem cells and their niches. This study therefore reveals the potential of adult tissue-derived hair follicle stem cells as a bioengineered organ replacement therapy.

(a) Schematic representation of the method used to generate and transplant bioengineered hair follicle embryos. (b) Phase-contrast images of mouse embryo dorsal skin, tissue, dissociated single cells and bioengineered hair follicle embryos reconstructed using the organ-germ method with nylon threads (arrowheads). Scale, 200 μm. (c) Histological analysis of isolated tentacles from adult mice. Macroscopic and H&E-stained tentacles are shown in the left two panels. The dashed line (red) from macromorphological observation (left) and H&E staining (right) indicates the interface of the bulge and SB regions. The boxed area in the left panel was H&E stained to show the bulge and the SB area is shown at higher magnification in the right panel. The bulge region was immunostained with anti-CD49f (red, left) and anti-CD34 (red, middle) antibodies and Hoechst 33258 dye (blue). The dashed black line in high magnification H&E indicates the epithelial interface of the hair follicle. IF, funnel; RW, annulus; half of follicle. Scale, 100 μm. (d) Histological and ALP analysis of the bulb area of ​​the tentacle and the initial culture of DP cells. Hair bulbs (2 left) and cultured DP cells (2 right) were analyzed by enzymatic staining for ALP. The red dotted line indicates the Auber line. Scale“, 100 μm. (e) Longitudinal section of the bioengineered hair during the eruption and growth process mediated by the interepithelial tissue connecting plastic device (with guide). Shown as cyst formation with bioengineered-generated follicles 14 days after engraftment H&E staining of bioengineered-generated follicles at days 0, 3 and 14 post-implantation (top) and fluorescence microscopy (bottom) Scale, 100 μm (f) Immediately after transplantation on day 0 (left), wound healing on day 3 (middle), and hair shaft eruption on days 14 and 37 (right). , and macromorphological observations of bioengineered breast (top) and spleen (bottom) development and growing hair during growth, scale, 1.0 mm.

(a) Histological and immunohistochemical analysis of bioengineered hair (top) and tentacle (middle) follicles. Boxed areas in low-magnification H&E panels are shown at higher magnification in right panels. Arrows indicate sebaceous glands. Scale, 100 μm. Hair bulbs of bioengineered hair follicles were immunostained with anti-versican (bottom left) and α-SMA (arrowhead, bottom right) antibodies and also enzymatically stained for ALP. (Bottom center) Scale, 50 μm. (b) Bioengineered human hair produced by transplantation of biotreated follicle embryos reconstituted by bulge-derived epithelial cells and intact DP of human scalp hair follicles. Twenty-one days after transplantation, bioengineered human hairs were photographed (microscopy) and analyzed by H&E staining. Species identification of bioengineered hair follicles was analyzed according to nuclear morphological features (right panel). The boxed area in the inset is shown at higher magnification. Scale, microscope 500 μm, H&E 100 μm, nuclear stain 20 μm. (c) High-density intradermal implants of bioengineered follicular pathogens. A total of 28 independent bioengineered hair follicle germs were implanted into the cervical skin of mice and showed dense hair growth 21 days after implantation. Scale, 5 mm.

Bioengineered hairs and tentacles were connected with other tissues such as nerve fibers, retractor muscles and striatum muscles derived from host or donor cells. The bioengineered hair bound smooth muscle as a result of regeneration of the NPNT-expressing bulge region, similar to the natural mass. Neither NPNT expression nor smooth muscle binding was detected in the bioengineered hair bulge region.

Quote/ 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