About Stem Cell Therapy

Indiva Clinic complies with the regulations of the Ministry of Health, Labour and Welfare's Act on the Safety of Regenerative Medicine and has obtained the second type of regenerative medical treatment provision plan number.

What are Stem Cells?

All of us have cells in our bodies that have the ability to regenerate lost cells to maintain tissues with short-lived cells, such as skin and blood, which are constantly renewing. These cells with such capabilities are called "stem cells." To be called a stem cell, the following two abilities are essential: one is the ability to produce various cells that make up our bodies, such as skin, red blood cells, and platelets (differentiation ability), and the other is the ability to divide into cells with the same capabilities as themselves (self-renewal ability).
There are broadly two types of stem cells. One type is stem cells that continue to create replacement cells in specific tissues or organs, such as skin and blood. This type of stem cell is called a "tissue stem cell." Tissue stem cells are not capable of becoming anything; they are restricted to certain roles, such as hematopoietic stem cells that produce blood cells or neural stem cells that produce neural cells. The other type is "pluripotent stem cells," such as ES cells (embryonic stem cells), which can create any type of cell in our body. In other words, pluripotent stem cells can also create various tissue stem cells in our bodies. Induced Pluripotent Stem Cells (iPS cells) are artificially created "pluripotent stem cells" derived from ordinary cells.
Using the properties of these "stem cells," research is progressing on new treatments called "regenerative medicine" that use the cells themselves as medicines to heal injuries and diseases, and on research to reproduce the state of cells in the body outside the body to investigate the mechanisms of diseases.

Effect of MSC transplantation on diabetic cardiomyopathy. (a) MSCs enhance the activation of MMP-2 and inhibit the activation of MMP-9, attenuating cardiac remodeling. (b) MSCs generate VEGF, IGF-1, AM, and HGF, stimulating muscle formation and angiogenesis in damaged myocardium. (c) Through differentiation into cardiomyocytes and endothelial cells, MSCs improve myocardial perfusion and regeneration. Abbreviations: AM, adrenomedullin; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; MMP, matrix metalloproteinase; MSC, mesenchymal stem cells; VEGF, vascular endothelial growth factor.

Effect of MSC treatment on diabetic polyneuropathy. Four weeks after intramuscular injection, MSCs deposit in the gaps between muscle fibers through the production of bFGF and VEGF, inducing angiogenesis and supporting neuronal regeneration that leads to the improvement of diabetic polyneuropathy. Abbreviations: bFGF, basic fibroblast growth factor; MSC, mesenchymal stem cells; VEGF, vascular endothelial growth factor.

Systemic administration of mesenchymal stem cells can induce endocrine (endocrine) or local (paracrine) effects, including cell-mediated actions. 1) Vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), monocyte chemotactic protein 1 (MCP1), basic fibroblast growth factor (bFGF), interleukin 6 (IL6) 2) Stem cell proliferation and differentiation: stem cell factor (SCF), leukemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), stromal cell-derived factor 1 (SDF1), angiopoietin 1, activin A 3) Inhibition of fibrosis: hepatocyte growth factor (HGF), bFGF, adrenomedullin (ADM) 4) Inhibition of apoptosis: VEGF, HGF, IGF1, transforming growth factor (TGF) β, bFGF, granulocyte-macrophage colony-stimulating factor (GM-CSF), activin A, thrombospondin 1. Immune-mediated actions include (5-8) 5) Inhibition of T and B cells: human leukocyte antigen G5 (HLA G5), HGF, inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE 2), bFGF, TGFβ 6) Induction and proliferation of regulatory T cells (Treg) through TGFβ expression. 7) Inhibition of natural killer (NK) cells by secretion of IDO, PGE 2, and TGFβ. 8) Inhibition of dendritic cell (DC) maturation by secretion of PGE 2.
Figure "Stem Cell Res Ther" was reproduced by Carrión and Figueroa. May 11, 2011; 2(3): 23.

Note: Red arrow: stimulation, black arrow: inhibition, arrow without a hook: direct inhibition.
Abbreviations: iDC, immature dendritic cell; IL, interleukin; HGF, hepatocyte growth factor; TGF-β, transforming growth factor-β; PGE-2, prostaglandin E2; IDO, indoleamine 2,3-dioxygenase; NO, nitric oxide; PD-L1, programmed death ligand 1; hMSC, human mesenchymal stem cell; Treg, T regulatory; Th, T helper; CTL, cytotoxic T cell; mDC, mature dendritic cell; PD-1, programmed cell death protein 1; PMN, polymorphonuclear leukocyte; NK, NK cell.

Images of sagittal (left) and coronal (right) planes of merged SPECT/CT images on days 1 (a), 2 (b), and 7 (c) showing local uptake in the anterolateral region of the heart in animals. At the final imaging time point (days 5-8), the anteroseptal region of MSC uptake (arrows) is shown in representative animals in the coronal plane. An anterior apex distribution existed regardless of whether an initial focal hotspot was observed or not (only the yellow arrow in f).

Characteristics of isolated bone marrow stromal cells. The cells were cultured from bone marrow after density fractionation, shown as (A) 48 hours after plating and (B) 10 days after plating. (C) Flow cytometry demonstrates enrichment of these cultured cells. Results were obtained on days 2, 5, and 14 of culture using antibodies against surface markers SH2 and SH3. By day 14, the cells were 95-99% homogeneous and negative for antigens common to hematopoietic cells, CD14, CD34 (Becton-Dickinson), or CD45 (Pharmingen). (D) Homogeneity and reproducibility of the isolation procedure were demonstrated by flow cytometry.

By DiseaseAge-Related Diseases

Pluripotent stem cells have remarkable self-renewal capabilities and can differentiate into multiple diverse cell types. There is growing evidence that the aging process may negatively impact stem cells. As stem cells age, their regenerative capacity declines, and their ability to differentiate into various cell types changes. Therefore, the decline in stem cell function due to aging is suggested to play an important role in the pathophysiology of various aging-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 therapies for future aging-related diseases. This review article focuses on the basis of stem cell dysfunction associated with various aging-related diseases. Next, some concepts about the mechanisms that may cause aging-related stem cell dysfunction are discussed. Also, current potential therapies for aging-related stem cell deficiencies under development are briefly discussed.
Citation// World J Exp Med. 2017 Feb 20; 7(1): 1–10. Effect of aging on stem cells. Abu Shufian Ishtiaq Ahmed, et al.

By DiseaseLiver/Diabetes

Regenerative medicine is transitioning to clinical programs using stem cell/progenitor cell therapy for repairing damaged organs. Briefly describe bile duct stem cells (hBTSC) located in the bile ducts, organs shared by the liver and pancreas, which share endodermal stem cell populations. They are precursors of liver stem/progenitor cells in Hering's canal and pancreatic duct progenitors. They give rise to a maturation lineage along the radial axis within the bile duct wall and a proximal-distal axis that begins in the duodenum and ends in mature cells in the liver or pancreas. Clinical trials evaluating the effects of stem cells (liver stem/progenitor cells derived from fetal liver) transplanted into the hepatic artery of patients with various liver diseases have been conducted over the years. Immunosuppression was not necessary. All control subjects given the criteria died or experienced decreased liver function within a year. Subjects transplanted with 100-150 million liver stem/progenitor cells showed improved liver function and survival over several years. Evaluations of the safety and efficacy of the transplantation are still under development. Stem cell therapy for diabetes using hBTSC is still being researched, but it is likely to be conducted after ongoing preclinical trials. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used in patients with chronic liver disease or diabetes. MSCs demonstrate effects through paracrine secretion of trophic and immunomodulatory factors, with limited inefficient lineage restriction to mature parenchymal or islet cells. The effects of HSCs are mainly due to the regulation of 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
http://dx.doi.org/10.1155/2016/4612167

Figure 1: Mechanism of the effect of MSC transplantation on diabetic PAD. The recovery effects mediated by stem cell transplantation from two pathways: one is the secretion of angiogenic factors and cytokines, and the other is the transplantation and differentiation of cells into tissue components. Stem cells can specifically enhance the local secretion and expression of angiogenic factors and cytokines, contributing to the reconstruction of the microcirculatory system, improvement of blood flow, and function of pancreatic islet β-cells, leading to the improvement of diabetic PAD. Stem cells can also differentiate into endothelial cells to achieve recovery of endothelial cell dysfunction. These effects may be related to miRNA and MEX.

Figure 2: Mechanism of the effect of MSC transplantation on diabetic wounds. Diabetic wound recovery through 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 the transplantation and differentiation of cells into tissue components. Stem cells can specifically enhance the local secretion and expression of angiogenic factors and cytokines, contributing to the improvement of diabetic PAD and diabetes. Stem cells can also regulate the activity of T cells, natural killer cells, macrophages, and dendritic cells, inhibiting infection and inflammatory responses. Furthermore, MSCs can differentiate into target tissues and achieve repair. These effects may be related to miRNA and MEX.

Figure 3: Mechanism of the effect of MSC transplantation on diabetic neuropathy. The recovery effects mediated by stem cell transplantation from two pathways: one is the secretion of angiogenic factors, cytokines, and neurotrophic factors, and the other is the transplantation and differentiation of cells into tissue components. Stem cells can specifically enhance the local secretion and expression of angiogenic factors and cytokines, contributing to the improvement of diabetic PAD and diabetes itself, leading to the improvement of diabetic neuropathy. Neurotrophic factors can also improve nerve fiber dysfunction and nerve conduction. Furthermore, stem cells can differentiate into target tissues and achieve repair.
Kidney Failure
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

Animals receiving mesenchymal stem cell therapy showed a reduction in stenosis – kidney microvascular loss and fibrosis. Top: Representative micro-CT 3D images of kidney segments showing improved microvascular structure in pigs with atherosclerotic renal artery stenosis undergoing percutaneous transluminal renal angioplasty (PTRA) and intrarenal MSC injection four weeks earlier. Bottom: Representative renal trichrome staining (×40, blue) showing reduced fibrosis in ARAS + PTRA + pigs MSC.

Clinical Applications of MSC: Diabetes

Stem cell transplantation may be a safe and effective treatment for patients with DM. In this series of trials, the best treatment outcomes for T1DM were achieved with D34 + HSC therapy, while the worst results for T1DM were observed with HUCB. Diabetic ketoacidosis hinders treatment effectiveness.

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 12 months after the administration of different types of stem cells. UC-MSC and PD-MSC were intravenously injected (n = 22 and n = 10, respectively), while UCB and BM-MNC were injected into the pancreas (n = 3 and n = 107, respectively). (E-F) Line graph showing changes in C-peptide and HbA1c levels at baseline, 3 months, 6 months, and 12 months after stem cell therapy for T2D.
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.

By DiseaseHair Follicles

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.
Summary
Organ replacement regenerative medicine is said to enable the replacement of damaged organs due to disease, injury, or aging in the foreseeable future. Here we demonstrate fully functional organ regeneration through intradermal transplantation of bioengineered germ and spore buds. These germ layers and buds are reconstructed with cells derived from embryonic skin cells and adult stem cell niches, respectively. The bioengineered hair follicles develop the correct structure and form appropriate connections with surrounding host tissues such as the epidermis, hind limb muscles, and nerve fibers. Bioengineered hair follicles also show restored hair cycles and hair bulb formation through the reorganization of hair follicle stem cells and their niches. Thus, this study reveals the potential of bioengineered organ replacement therapy using adult tissue-derived hair follicle stem cells.

(a) Schematic diagram of methods used for the creation and transplantation of bioengineered hair follicle buds. (b) Phase-contrast images of dorsal skin, tissue, dissociated single cells, and bioengineered hair follicle buds of a mouse embryo reconstructed using the organ bud method with nylon thread (arrowhead). Scale bar, 200 μm. (c) Histological analysis of whiskers isolated from adult mice. Macroscopic and H&E staining whiskers are shown in the left two panels. The dashed lines (red) in the macroscopic observation (left) and H&E staining (right) indicate the interface of the bulge and SB regions. The boxed area of the left panel is shown at higher magnification in H&E staining to demonstrate the bulge and SB regions in the right panel. The bulge region is immunostained with anti-CD49f (red, left) and anti-CD34 (red, center) antibodies and Hoechst 33258 dye (blue). The black dashed line in the high-magnification H&E shows the interface of the epithelium of the hair follicle. IF, infundibulum; RW, ring body; half of the hair follicle. Scale bar, 100 μm. (d) Histological and ALP analysis of the bulb region of whiskers and initial cultures of DP cells. The hair bulbs (left two) and cultured DP cells (right two) were analyzed by ALP enzyme staining. The red dashed line indicates Auber's line. Scale bar, 100 μm. (e) Longitudinal section of bioengineered hair during the process of eruption and growth mediated by the epithelium-mesenchyme interaction plastic device (guided). The corresponding one is shown as cyst formation with bioengineered hair follicles 14 days after intradermal transplantation (without guide). H&E staining (top) and fluorescence microscopy (bottom) of bioengineered hair follicles at days 0, 3, and 14 after transplantation. Scale bar, 100 μm. (f) Macroscopic observation of bioengineered hair follicles during the growth and development process from the chest (top) and spleen (bottom) of the generated hair including wound healing at day 0 (left), healing at day 3 (center), eruption of the hair shaft at days 14 and 37 (right), and growth. Scale bar, 1.0 mm.

(a) Histological and immunohistochemical analysis of bioengineered hair (top) and whisker (middle) follicles. Boxed areas of the low-magnification H&E panels are shown at higher magnification on the right. Arrows indicate sebaceous glands. Scale bar, 100 μm. The hair bulb of bioengineered hair follicles is immunostained with anti-versican (bottom left) and α-SMA (arrowhead, bottom right) antibodies and enzymatically stained for ALP (bottom center). Scale bar, 50 μm. (b) Bioengineered human hair follicles produced by transplantation of bioengineered hair follicle buds were reconstructed with epithelial cells derived from the bulge and intact DP of human scalp hair follicles. Bioengineered human hair was observed (microscopic observation) and analyzed by H&E staining at day 21 post-transplantation. Species identification of bioengineered hair follicles was analyzed according to nuclear morphological characteristics (right panel). The boxed area in the inset is shown at higher magnification. Scale bar, microscopy 500 μm, H&E 100 μm, nuclear staining 20 μm. (c) High-density intradermal transplantation of bioengineered hair follicle buds. A total of 28 independent bioengineered hair follicle buds were transplanted into the cervical skin of mice, showing high-density hair growth at day 21 post-transplantation. Scale bar, 5 mm.

Bioengineered hair and whiskers were connected with other tissues such as nerve fibers, arrector pili muscles, and striated muscles derived from host or donor cells. Bioengineered hair connected to smooth muscle as a result of the regeneration of the bulge region expressing NPNT similarly to natural bulges. Neither NPNT expression nor smooth muscle connection was detected in the bulge region of bioengineered hair.
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

By DiseaseParkinson&#39;s

Schematic diagram of the induction, differentiation, and application of currently available stem cells in PD research and therapy. The above stem cells can be divided into four categories: ESC, NSC, MSC, and iPSC, with gradually decreasing differentiation potency. (1) ESCs, mainly derived from the inner cell mass of blastocysts, can differentiate into endoderm, mesoderm, and ectoderm simultaneously under normal conditions. In some cases, ESCs can also be induced to differentiate into NSCs and MSCs. (2) NSCs isolated directly from specific brain niches or reprogrammed from fibroblasts can differentiate into neurons and almost all glial cells of the nervous system. (3) MSCs are mainly derived from mesenchymal tissues and can differentiate into most cells of mesodermal origin. Notably, MSCs can also be induced to differentiate into DA neurons under specific combinations of induction protocols. (4) iPSCs, re-differentiated from adult human somatic cells (e.g., fibroblasts) by introducing OSKM (Oct3/4, Sox2, Klf4, and c-Myc), are a promising source of stem cells with multilineage differentiation potential. Based on GMP standards, the above stem cells and final differentiated cells can be further screened, purified, and expanded for application in disease models, drug screening, and CRT implementation. For example, ESCs, MSCs, NSCs, and DA neurons are used in the following. (i) Preparation of PD models (ii) Potential drug screening; (iii) CRT treatment of 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

Background:
Mesenchymal stromal cells (MSCs "adult stem cells") have been widely used experimentally in various clinical settings. Although there is interest in using these cells for serious illnesses, the safety profile of these cells is not well known. We conducted a systematic review of clinical trials examining the use of MSCs to evaluate their safety.
Methods and Results:
We searched MEDLINE, EMBASE, and CENTRAL (until June 2011). Clinical trials using intravascular delivery (intravenous or intra-arterial) of MSCs in adults or mixed groups of adults and children were conducted. Studies using differentiated MSCs or additional cell types were excluded. Primary outcomes were classified according to immediate events (acute infusion toxicity, fever), organ system complications, infections, and longer-term adverse events (death, malignancy). 2347 citations were reviewed, and 36 studies met the inclusion criteria. Among the 1012 participants were patients being treated for ischemic stroke, Crohn's disease, cardiomyopathy, myocardial infarction, graft-versus-host disease, and healthy volunteers. Eight studies were randomized controlled trials (RCTs) with 321 participants.
Citation// PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25.
Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group.

Clinical trial with control: stem cell therapy outcome related variables.

Ref= reference number, T2DM= Type 2 diabetes mellitus, treatment control allocation: 1 patient option, 2 successive: 2 Treatment – 1 Control, others: random, 3single blind multi center (18 –USA), 4=T2DM and T1DM, T= treatment, C= control, y= year(s), MNC= mononuclear cell, HBO= hyperbaric oxygen, MSC= mesenchymal stem cell, mo= month(s), wk= week(s)
SC= stem cell, Auto= autologous, BM= bone marrow, ?= data not available, DPA= dorsal pancreatic artery/substitute, M= million, SP/DA= superior pancreatic or duodenal artery, PB= peripheral blood, GCSF= granulocyte colony stimulating factor, IV- intra venous, P= passage, BW= body weight, B= billion, vit.= vitamin, SPDA= superior pancreaticoduodenal artery, UCB= umbilical cord blood, CC= corpora cavernosa (penile root clamped with a band 30 min), MPC= mesenchymal progenitor cell, cryo= cryopreserved, hu= human, HSC= haematopoietic stem cell, cryo= cryopreserved, D= diet, E= exercise, PST= previous standard therapy, BGM = blood glucose monitoring, MA= medication adjustment, IIT= insulin intensification therapy, L= lifestyle, SGBM= self blood glucose monitoring, IA= insulin adjustment, W-SGBM= weekly SGBM, D-SGBM= daily SGBM (minimum 5 points/week), RT= rescue therapy using oral antidiabetic agent, except thiazolidinediones in case there was unacceptable hyperglycemia, FU= at follow up
Current Stem Cell Research & Therapy, 2018(13)
Towards Standardized Stem Cell Therapy in Type 2 Diabetes Mellitus: A Systematic Review
Jeanne Adiwinata Pawitan, Zheng Yang, Ying Nan Wu and Eng Hin Lee
[20]Hu J, Li C, Wang L, et al. Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus. Endocr J 2012; 59(11): 1031-9.
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[22] Bhansali A, Asokumar P, Walia R, et al. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant 2014; 23(9): 1075-85.
[23] Bhansali A, Upreti V, Khandelwal N, et al. Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev 2009; 18(10): 1407-16.
[24] Hu J, Wang Y, Gong H, et al. Long term effect and safety of Wharton's jelly-derived mesenchymal stem cells on type 2 diabetes. Experimental and Therapeutic Medicine 2016; 12 (3): 1857-66.
[25] Bahk JY, Jung JH, Han H, Min SK, Lee YS. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. Exp Clin Transplant 2010; 8(2): 150-60.
[26] Skyler JS, Fonseca VA, Segal KR, et al. Allogeneic mesenchymal precursor cells in type 2 diabetes: A randomized, placebo-controlled, dose-escalation safety and tolerability pilot study. Diabetes Care 2015; 38(9): 1742-9.
[27] Ghodsi M, Heshmat R, Amoli M, et al. The effect of fetal liver-derived cell suspension allotransplantation on patients with diabetes: first year of follow-up. Acta Med Iran 2012; 50(8): 541-6.