Abstract

INTRODUCTION
Mesenchymal stem cells (MSCs) are rare multipotent stem cells of mesenchymal origin, and were first described as fibroblast precursors form bone marrow by Friedenstein et al. in 1970 ¹. They were found to exist not only in bone marrow but also in virtually all organs including umbilical cord (UC), placenta, fat, muscle and cartilage ² , ³ , ⁴. For better characterization of MSC, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) defined MSCs by the following three criteria: (i) adherence to tissue culture plastic; (ii) positivity for CD105, CD73 and CD90, and negative for CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR; (iii) ability to differentiate into osteoblasts, adipocytes and chondroblasts under standard in vitro differentiating conditions  ⁵. The isolated MSCs can expand to clinical scales in a relatively short period of time. The multi-lineage differentiation ability of MSCs, together with their relatively easy isolation and their extensive capacity for in vitro expansion, has led to important approaches in utilizing MSCs for clinical therapy in a variety of congenital and acquired diseases. Most importance of all, clinical studies so far showed no serious adverse reactions associated with autologous and allogeneic MSC therapy, providing some assurance to investigators that this innovative therapy appears safe  ⁶.

It has been more than thirty years since the first allogeneic bone marrow transplantation was successfully performed for the treatment of severe alplastic anemia in Peking University People’s Hospital, which marks an important milestone for the stem cell clinical translation in China. Hematopoietic stem cell(HSC) transplantation has cured many patients suffering from hematological diseases in China. However, this progress cannot tackle the healthcare challenge faced by Chinese people. With economic modernization, cancer and heart disease have rapidly become the leading cause of death for Chinese people today; diabetes and liver diseases affect 92.4 million and 100 million Chinese population, respectively  ⁷ , ⁸; and neurological disorders are also on the rise. Therefore, an urgent need exists for clinical translation of stem cell research to better meet the needs of patients suffering a broad spectrum of diseases. Moreover, the Chinese population is highly supportive of new medical technology, which includes using somatic cells, particularly for currently untreatable or incurable conditions. In recent years, MSC-based clinical trials have been vigorously carried out across the world. Among these areas, China has made great strides in stem cell research, from annual publications in the stem cell field to steeply increasing clinical trials. China has a growing number of world-class scientists in stem cell research, but has also been widely criticized for its perceived obscure laws and regulations with respect to stem cell research and its clinical translation  ⁹ , ¹⁰ , ¹¹. This review will provide an overview of the recent clinical findings in China related to MSCs, as well as clinical and translational regulations.

Clinical application of MSCs

We have previously reviewed the mechanisms underlying immunomodulation and tissue repair by MSCs in detail  ¹². Briefly, the potential clinical use of MSCs relies on their several key properties: (i) their capacity to support hematopoiesis. MSCs are important component of HSC niche, and they promote the growth, survival and differentiation of HSC and progenitor cells by producing various growth factors and matrix proteins  ¹³. (ii) their capacity to differentiate into various cell lineages. MSCs are multipotent cells that can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma and muscle  ¹⁴. Studies  ¹⁵ , ¹⁶ , ¹⁷ have also indicated that MSCs can transdifferentiate into cells of other lineages, including islet-like cells, multiple skin cell types, neuron-like cells; (iii) their ability to secrete soluble factors that are crucial for cell survival and proliferation and neovascularization, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), nitric oxide, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1 (SDF) ¹⁸ , ¹⁹ , ²⁰.  (iv) their ability to modulate immune response ²¹ , ²². MSCs exert their immunoregulatory effects on a large panel of effector cells of adaptive and innate immunity, including T cells, B cells, natural killer cells, monocytes/macrophages, dendritic cells and neutrophilsby direct cell-to-cell contact or/and release of soluble immunosuppressive factors. However, the exact mechanisms by which MSCs promote tissue regeneration may vary, depending on types of disease and injured tissues. In the past ten years, MSC transplantation for various diseases has become one of the most widely studied cell-based therapies in China, sometimes with encouraging results. Below is a brief description of the reported case reports and clinical trials related to MSCs in China.

Support of hematopoiesis

Allogeneic hematopoietic stem cell (HSC) transplantation is an effective therapy for a number of hematological diseases. As we mentioned above, MSCs secrete cytokines and provide a suitable microenvironment for the proliferation, differentiation and maturation of hematopoietic stem cells, thus MSCs have the ability to support and maintain hematopoiesis in vivo. Several groups in China have used MSCs for rapid or long-term hematopoietic reconstruction. In a pilot study, Wu et al. ²³ reported that bone marrow-derived MSCs (BM-MSCs) and peripheral blood stem cells (PBSC) cotransplantation was safe, and could lead to rapid hematopoietic reconstruction in five patients with hematological malignant diseases. In another trial reported by Zhang et al. ²⁴, from First Affiliated Hospital of Nanjing Medical University, rapid hematopoietic recovery was found for most patients receiving co-transplantation of allogenic cultured MSCs and HLA-identical sibling-matched HSCs. In a relatively larger clinical trial ²⁵ involving 55 patients with leukemia in complete remission, MSCs were found to facilitate platelet recovery without increasing leukemia recurrence in haploidentical HSC transplantation. Some large-scale, randomized clinical trials in China are currently underway to confirm these preliminary results (NCT01305694, 01182662, 01129739, 01763099).

In fact, BM-MSCs are altered in various hematologic disorders. Chinese researchers  ²⁶ , ²⁷ found that autologous BM-MSCs from patients with severe hematologic disease, such as aplastic anemia and acute myeloid leukemia (AML), were deficient in the ability to support hematopoiesis and cytokine release. Wu et al. ²⁸ investigated GATA gene expression of MSCs from chronic aplastic anemia patients and proposed that aberrant expression of these genes in BM-MSCs may influence the BM microenvironment and lead to abnormal hematopoietic regulation. At present, it is hard to determine a causative relation between abnormal MSCs and disease state. Considering the supportive effect of MSCs on hematopoiesis, MSC defects may be involved in the pathogenesis of hematological diseases. Conversely, BM-MSCs in some patients with hematological diseases might display aberrations and/or functional defects because of deregulated release of proinflammatory mediators and inhibitory cytokines by apoptotic hematopoietic cells into BM microenvironment. Thus, allogeneic stem cells might be a promising alternative for these patients with hematological diseases.

Promoting tissue repair

Cardiac Repair. Cardiovascular disease is now the most prevalent disease affecting the Chinese population. Despite advance progress in the drug prevention and treatment of heart diseases such as myocardial ischemia (MI) and heart failure, mortality and morbidity rates remain high. A large body of literatures recorded in English and Chinese indicated that MSCs transplantation may improve recovery of cardiac function after MI. Chen et al. at Nanjing University began the first clinical trial of MSC therapy for acute MI in China. In this randomized clinical trial, sixty-nine patients with acute MI after percutaneous coronary intervention were randomized to receive either intracoronary injection of BM-derived MSCs or control vehicle. MSCs significantly increased the left ventricular ejection fraction three months after transplantation compared to the control group. MSC transplantation was safe with no deaths or malignant arrhythmias ²⁹ , ³⁰. Since then, a number of clinical trials ³¹ , ³² , ³³ have been performed in China to test the safety and efficacy of MSC transplantation for the treatment of MI and chronic ischemic cardiomyopathy. Wang et al. ³⁴ conducted a prospective, randomized, controlled trial to explore the efficacy and safety of autologous MSC transplantation via intracoronary delivery for treating patients with idiopathic dilated cardiomyopathy. Six months later, patients showed a significant improvement in their six-minute walking test scores, whereas their left ventricular ejection fraction and left ventricular end diastolic diameter remained unchanged. In fact, in the past ten years researchers in China havetried to cure ischemic heart diseases with various cells (MSCs derived from BM-mononuclear cells, MNC, PBSC, or by G-CSF mobilization) and/or different approaches (i.e. via intravenous, intracoronary andintramyocardial deliveries). The great challenge for the future is to determine the optimal cells type, time window and therapeutic approach for the individual patient.

Neural Repair. The neural differentiation potential of MSCs, together with their trophic and immunoregulatory properties, renders MSCs as a potential therapeutic for a variety of neural insults. A clinical study performed by Zhang et al. ³⁵ at Weifang People’s Hospital tested the transplantation of cultured autologous BM-MSCs in seven patients with traumatic brain injury. In this study, all patients received a primary administration of 107-109 cells that were directly injected to the injured area during the cranial operation and a second dose of 108-1010 cells that was infused intravenously. MSC therapy significantly improved neurologic function at 6 months, as evidenced by an increased Barthel Index. Chen et al. ³⁶, at the Second Military Medical University, firstly reported a controlled clinical trial of neural stem cell–like cells derived from autologous BM-MSCs as a novel treatment for patients with moderate-to-severe cerebral palsy. This study provides strong clinical evidence that supports stem cell transplantation for the treatment of motor deficits related to cerebral palsy. In addition, MSCs were tried for treating hereditary spinocerebellar ataxia. At the Drum Tower Hospital of Nanjing University, sixteen genomically diagnosed spinocerebellar ataxia patients received intravenous and intrathecal infusion of UC-MSCs. Most patients showed improved the Berg Balance Scale and the International Cooperative Ataxia Rating Scale (ICARS) scores continuing for at least 6 months which indicated UC-MSC therapy could alleviate symptoms of spinocerebellar ataxia ³⁷. However, the transdifferentiation potential of MSCs to neurons, remains controversial and needs further evaluation ³⁸.  It should be noted that although some small, well thought out clinical trials are being planned and undertaken, further studies are warranted to determine the long-term safety and effectiveness of these therapies in a broad range of neurological diseases, such as Parkinson’s disease.

Liver diseases. HBV infection is a leading cause of illness and death in China. Each year, an estimated 263,000 persons in China die from HBV-related end stage liver diseases, accounting for 37%~50% of HBV-related deaths worldwide ³⁹. There is no effective treatment currently available, except for liver transplantation. However, serious problems are associated with liver transplantation, such as shortage of donors, rejection, serious surgical complications and high cost. Jiang et al. ⁴⁰ presented the first report of transdifferentiation of MSCs into hepatic cells in vitro, after which researchers worldwide and in China presented evidence in support of therapeutic potential of MSCs for liver regeneration. Chinese researchers found that MSCs have a significant impact on hepatic fibrogenesis through their ability of inhibiting activated hepatic stellate cells, which is crucial to liver fibrosis, and re-regulating the fibrogenic process ⁴¹. Zhang et al. ⁴² at the Beijing 302 Hospital reported 45chronic hepatitis B patients with decompensated liver cirrhosis that received multiple intravenous MSC infusions or saline. In this open-labeled, paired, controlled study, UC-MSCs injection improved the clinical indices of liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels and reduction in the volume of ascites. In another clinical study at the Beijing 302 Hospital ⁴³, 43 patients with hepatitis B virus-related acute-on-chronic liver failure were injected cultured UC-MSCs. The UC-MSC transfusions significantly improved the survival rates, reduced the model for end-stage liver disease (MELD) scores, increased serum albumin, cholinesterase, prothrombin activity and platelet counts in these patients. There are several routines for MSC administration, including via peripheral vein, hepatic artery and portal vein. Portal vein or hepatic artery delivery may enhance MSC homing efficacy, however, precautions must be taken in view of the portal hypertension and the presence of ascites in most patients with liver cirrhosis.

Bone/cartilage diseases. The capability of the MSCs in repair and regeneration of mesenchymal tissues has also been widely studied including bone/cartilage defect regeneration. Zhao et al. ⁴⁴ from Dalian University of Technology investigated the feasibility of autologous BM-MSC transplantation in 53 patients with early-stage osteonecrosis of the femoral head. BM-MSC treatment significantly improved the Harris hip score (HHS) as well as decreased the volume of the necrotic lesion compared with preoperative condition. MSCs were usually used to repair bone defects alone or in combination of scaffolds. Recently, the approach that combines regenerating cells such as MSCs, bioactive matrices, and osteoinductive growth factors are being investigated for the treatment of joint cartilage/bone defects. Advances in the field of biomaterials have led to a transition from nonporous, biologically inert materials to more porous, osteoconductive biomaterials, and, in particular, the use of cell-matrix composites, such as porous ceramics of hydroxyapatite and β-tricalcium phosphate. Gan et al. ⁴⁵ from Shanghai Jiaotong University explored the feasibility of the BM-MSCs combined with porous beta-tricalcium phosphate (beta-TCP) for posterior spinal fusion in 41 patients. The results showed that enriched MSCs could adhere to the wall of porous beta-TCP within 2h, and proliferate well during culture in vitro. After 34.5 months, 95.1% of patients had good spinal fusion results. Chen et al. ⁴⁶ showed that co-cultured BM-MSCsand periosteal-derived stem cells (hPCs) resulted in a synergistic effect on osteogenic differentiation both in vitro and in vivo. Eight weeks after implantation of beta-TCP that load with MSCs and hPCsat 1:1 ratio, cocultured hBMSCs and hPCs not only increased osteoblastic mineralization and enhanced bone regeneration, but accelerated the neovascularization of bone.

Diabetes and its complications. The Chinese researchers have investigated the therapeutic effects of MSCs on both type 1 and type 2 diabetes mellitus. In a pilot clinical trial ⁴⁷ with a small number of participants, transplantation of placenta-derived MSCs resulted in significant decrease in the insulin dose requirement along with improvement in the stimulated C-peptide levels in type 2 diabetic patients. Hu et al. ⁴⁸ at Qingdao University assessed the long-term effects of the implantation of Wharton’s jelly-derived MSCs (WJ-MSCs) for treating newly-onset type1 diabetes. The results showed an improvement of metabolic control (HbA1c, C-peptide) in the patients who treated with MSCs, indicating that MSCs can restore the function of islet β cells in a longer time. Diabetic ulcer in lower extremity, which is often subject to poor vascularization with localized hypoxia, is one of the most common complications of diabetes. Treatment of these chronic wounds remains difficult. Preclinical and clinical studies showed that MSCs can accelerate wound repair or even reconstitute the wound bed. MSCs are likely contributed to chronic wound healing by several mechanisms. Most important of all, MSCs secrete many cytokines beneficial to wound healing which include IGF-1, EGF, VEGF, PDGF, HGF, SDF-1 and angiopoietin. Many Chinese researchers have investigated the therapeutic effects of MSCs on lower extremity diabetic ulcers in animal models ⁴⁹. Their results indicate that MSCs are effective in increasing blood flow in the ischemic legs and can accelerate the healing process of the wounds. A double-blind, randomized, controlled trial conducted by Lu et al. ⁵⁰ showed that BM MSCs therapy might be better tolerated and more effective than BM-MNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients. Interestingly, Chinese investigators reported that MSCs can contribute to the healing of injured skin appendages, such as sweat glands ⁵¹ , ⁵². Tao et al. ⁵³ successfully induced the phenotypic transformation to sweat gland cells from UC-MSCs by culturing in  epimorphin-conditioned medium. Delivery of MSCs for wound therapy may be done by direct application to the wound bed, injection into the periphery of the wound, or within a variety of matrices or biosynthetic materials. The latter of which may assist in cellular retention as well as direct differentiation capacity within the wound.

Alleviation of immune-related disorders

Graft-versus-host Disease (GVHD). The most significant findings related to the immunosuppressive effects of MSCs so far have been observed in the prevention and treatment of steroid-resistantacute or chronic GVHD after allogeneic bone marrow transplantation. At present, GVHD remains a major cause of morbidity and mortality after allogeneic HSC transplantation. MSCs can modulate immune responses and lead to resolving of GVHD. Chinese researchers have currently completed several phase I & II clinical studies to test the efficiency of MSCs in treating steroid-resistant acute or chronic GVHD ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹. Weng et al. ⁶⁰ from Guangdong General Hospital reported that BM-MSCs derived from HLA-identical sibling donors were effective as a salvage therapy for refractory chronic GVHD. In this study, 14 of 19 patients (73.7%) responded well to BM-MSCs. The immunosuppressive agent could be tapered to less than 50% of the starting dose in 5 of 14 surviving patients, and five patients could discontinue immunosuppressive agents. Fang et al., at Henan Institute of Hematology, isolated MSCs from fat tissue and used them to successfully treat GVHD in several clinical settings ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵, providing a less invasive alternative of BM-derived MSCs.

Organ transplantation. MSCs may also offer therapeutic opportunities in organ transplantation by inhibiting T-cell proliferation, cytotoxic T- lymphocyte activity, B cell activation and differentiation and DC maturation and thereby blunting the effector arm of the alloresponse ⁶⁶. At our institute, 1-2 ×106 MSC/kg recipient body weight were infused at the time of renal transplantation and at two weeks post transplant respectively. The results indicated that induction therapy with MSC appeared to be more effective than anti-IL-2 receptor antibody in the prevention of acute rejection and was associated with better clinical outcomes as far as early renal graft function and rate of infections. Thus, MSCs may replace a powerful anti-rejection drug in transplant recipients ⁶⁷. Last year, Beijing 302 Hospital launched a clinical study to assess UC-MSCs as replacement of immunosuppressive agents for liver transplanted recipients. This study is currently recruiting participants.

Chronic inflammatory autoimmune diseases. In China, systemic lupus erythematosus (SLE) is one of most studied autoimmune diseases that treated by MSCs based on its immune regulatory properties. SLE is a chronic inflammatory connective tissue disorder characterized by the presence of various autoantibodies, and it affects multiply organs such as joints, kidneys, skin. The previous animal studies demonstrated that MSCs have shown promise in exerting an immediate anti-inflammatory immunomodulatory role in SLE model. Clinical studies for refractory SLE patients using allogeneic MSCs at the Drum Tower Hospital of Nanjing University demonstrated amelioration of disease activity, improvement in serological markers and stabilization of renal function ⁶⁸ , ⁶⁹. In another report by the same group, they investigated whether the immunoregulatory effect of MSCs on T cells or B cells was in a dose-dependent manner. Interestingly, single allogenic MSC transplantation at the dose of one million MSCs per kilogram of body weight is sufficient to induce disease remission for refractory SLE patients, and repeated MSCs transplantations failed to enhance therapeutic effect compared with single transplantation in SLE ⁷⁰. Chinese researchers have also addressed the interactions between MSCs and immunosuppressive drugs, which are commonly used in patients with autoimmune diseases. For example, based on the evidence provided by Shi et al. ⁷¹, MSCs facilitate the immunosuppressive effect of cyclosporine A on T lymphocytes. Thus, careful monitoring should be given to patients simultaneously receiving MSCs and immunosuppressants.

Ongoing clinical trials related to MSCs in China

By 2013/9/30, the public clinical trials database (http://clinicaltrials.gov) has showed 359 clinical trials using MSCs for a very wide range of therapeutic applications worldwide. Among these, 75 clinical trials conducted in Mainland China, accounting for one fifth of total. In fact, the clinical trials related to MSCs in China are far more than these, considering some were registered in local healthcare authorities, but not at http://clinicaltrials.gov. Some clinical trials are currently underway or in the participant recruitment phase (Table 1). We are pleased to find some large-scale, multicenter cooperative studies, which account for approximately 30% of the total.  However, most of MSC-based clinical trials in China are in Phase I and Phase II, or a mixture of PhaseI/II studies. Only a small number of these trials are in Phase III or Phase II/III. The ongoing clinical trials at various stages using MSCs include Parkinson’s Disease, stroke, rheumatoid arthritis, muscular dystrophy, ischemic cardiomyopathy, lupus nephritis, amyotrophic lateral sclerosis, ulcerative colitis.

Xu-Table 1

Law and regulations

China has a long history of stem cell research that can be traced back nearly half a century to1963, and is one of the first countries in the world to promulgate guidelines governing the production and research use of hESCs. In 2001-2003, China’s government has issued several guidelines to regulate human stem cell research, include guidelines on human assisted-reproductive technologies and ethical guidelines for human embryonic stem cells (ESC) research. At that time, very few medical practitioners have used human fetal tissues or stem cells to treat patients, except for HSC transplantation. Although advanced progress has been made in clinical translation of stem cells for various diseases in the last decade, clinical and translational regulations governing the use of stem cells in China have not yet fully developed. Before 2007, common somatic cells, including adult stem cells, were originally treated as “medical products” or “drugs” in China and thus were subject to approval by China’s State Food and Drug Administration (SFDA), the counterpart of the U.S. Food and Drug Administration (FDA). Around 2007, Ministry of Health published the guidelines, titled “Regulation on ethical review of biomedical research involving human subjects”, to monitor research and clinical trials using human subjects such as stem cells. Stem cell applications were meanwhile classified as a new medical technology and regulated by the Ministry of Health. In May 2009, the Chinese Ministry of Health formally announced that stem-cell treatments were classified as Category Three medical technologies, which are deemed “ethically problematic”, “high risk” or “still in need of clinical verification”. The ministry takes direct responsibility for oversighting all Category Three technologies, which include gene therapy, surgical treatment of mental disorders or drug addiction, and sex changes, and requires the sponsors to obtain prior approval from Ministry of Health or face legal consequences. Thus, allogeneic, autologous, and xenogeneic stem cell therapies were under the direct responsibility of the Chinese Ministry of Health. In late 2009, there are still lack clear regulations to guide the researchers using stem cells in the clinic.

For a long time, most of stem cell-based clinical trials in China have not applied for an approval from the SFDA or Ministry of Health. One important reason is that many researchers and institutes were not certain whether stem cells were a drug or a medical technique, thus they were unclear to whom they applied for the qualification of clinical use of stem cells, the SFDA, the Ministry of Health, or the Ministry of Science and Technology ⁷². They usually obtained approvals from the Ethics Committee of the institutes and hospitals, and sometimes they registered their trials in the Chinese Clinical Trial Registry system(http://www.chictr.org/cn/) and/or U.S. public clinical trials database (http://clinicaltrials.gov).

In the absence of clear clinical regulation, over 200 companies and hospitals have started clinical studies to offer stem cell administration to selected patients. Obviously, the safety and efficiency of the stem cell-based clinical trials may not be guaranteed without the supervision of the SFDA or Ministry of Health. In some hospitals, MSCs derived from different origins that were not well characterized were used for a variety of diseases. Thus oversight on stem cell products is urgently needed; otherwise the public’s health will be at risk. On January 10, 2012, China announced to halt any new applications for clinical trials of stem-cell products until July 1 as part of a year-long campaign to regulate the development of the industry. China is developing appropriate regulations and guidance documents to regulate the clinical translation of stem cell research and strengthen stem cell clinical trial management. In March 2013, the Ministry of Health and the SFDA jointly publicized the draft rules to solicit public opinions on regulations governing stem cell clinical trial management in order to protect the interests of providers and patients. The draft emphasizes the following important aspects:  i) All proposed clinical trials on stem cells would be subject to ethical review. ii) Researchers must submit relevant materials surrounding stem cell products, selection criteria, consent forms of providers and patients, safety evaluation reports, research plans, and resumes of main participating researchers to the ethical board for review. iii) Only top-level hospitals certified by the SFDA as eligible for carrying out drug clinical trials could apply for stem cell clinical trials. iv) Patients should not be charged during the first three phases of stem cell clinical experiments. Medical institutions that violate the rules will lose their qualification and face penalties. In addition, the country still needs to work out how to make law enforcement more effective.

Outlook

Although basic biological and animal experiments have been carried out by a large number of researchers in China, and more and more patient’s benefits from optimization and progress in stem cell transplantation technology, many fundamental questions remain unanswered. Directions for future research include the standardization and validation of the isolation and culture expansion method of MSCs used for laboratory based scientific investigations and clinical studies; unraveling the mechanism underlying the tissue repair and immunosuppressive effects of MSCs in order to optimize their potential therapeutic application; multi-center randomized clinical trials, to decide precise parameters during cell therapy such as optimal therapeutic time window, cell dose, appropriate route of delivery, and further assessment of clinical safety and efficacy; and investigation into the in vivo behavior of MSCs, to establish essential safety criteria in order to fully harness all potential clinical therapeutic benefits. In the near future we anticipate a rapid closure of the many gaps in our knowledge of MSCs, which may facilitate the development of phase II and III clinical trials for new therapeutic alternatives.

We all know that sound laws and regulations shall help to speed up the translation of stem cell research into the clinics. Dr. Ricordi discussed these topics especially on how to be as efficient as possible on the path to resolve current challenges in the delivery of novel cell based therapeutic strategies to cure disease conditions now afflicting humankind ⁷³. In some countries, all MSCs-based clinical trials should be conducted in compliance with the Good Clinical Practice (GCP) guidelines, which are provided by International Conference on Harmonisation (ICH). GCP is an international quality standard on how clinical trials should be conducted, including designing, conducting, monitoring and recording of clinical trials. Thus, compliance with this standard will provide assurance for both safety and efficacy of MSC-based therapy in clinical trials. In fact, China has made tremendous effort intended to build a truly world-class stem cell research enterprise, and it really made an impressive start. Chinese government has heavily funded stem cell research all the times. Since 1986, China launched a number of special national research initiatives, such as the High Technology R&D program (the 863 program) and basic science research program (known as the “973” plan), both administered by the Ministry of Science and Technology(MOST), and stem cell research and regenerative medicine are key areas receiving priority funding. National Natural Science Foundation of China (NSFC) has increased its budget for stem cell research year by year. As reported by Yuan et al. ⁷⁴, the national government’s stem cell research funding commitment is estimated at more than 3 billion RMB (closeto $500 million) in total over the next 5 years, and the amount excludes local government funding, industry support, and other initiatives. In 2011, China has released its 12th Five-year Plan (2011-2015) for Medical Technology, setting stem cell and regenerative medicine technology as key tasks. Through these efforts and work with international collaborators, China becomes a rising star in regenerative stem cell therapy, as evidence by a remarkable increasing number of clinical and basic research studies that have been published in influential journals or presented orally at the high-profile international stem cell conferences. Now, it is hoped that the new policies and regulations will come into effect soon in China, to sustain its rapid pace of development in stem cell research as well as its efforts that have borne fruit.  We believe through these efforts, China will have a promising future and contribute more to the world stem cell field.

Reference

1. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3(4): 393-403.  (back)
2. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-1477.  (back)
3. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119: 2204-2213.  (back)
4. Caplan Al. Mesenchymal Stem Cell. J Orthopaed Res 1991; 9(5): 641-650.  (back)
5. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315-317.  (back)
6. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC,  et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 2012; 7(10): e47559.  (back)
7. Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010; 362(12): 1090-1101.  (back)
8. Centers for Disease Control and Prevention (CDC). Progress in hepatitis B prevention through universal infant vaccination–China, 1997-2006. MMWR Morb Mortal Wkly Rep 2007; 56(18): 441-445.  (back)
9. No authors listed. Stem-cell laws in China fall short. Nature 2010; 467(7316): 633.  (back)
10. Cyranoski D. China’s stem-cell rules go unheeded. Nature 2012; 484(7393): 149-150.  (back)
11. Cyranoski D. Stem-cell therapy faces more scrutiny in China. Nature 2009; 459(7244): 146-147.  (back)
12. Wang J, Liao L, Tan J. Mesenchymal-stem-cell-based experimental and clinical trials: current status and open questions. Expert Opin Biol Ther 2011; 11(7): 893-909.  (back)
13. Wang X, Hisha H, Mizokami T, Cui W, Cui Y, Shi A, et al. Mouse mesenchymal stem cells can support human hematopoiesis both in vitro and in vivo: the crucial role of neural cell adhesion molecule. Haematologica 2010; 95(6): 884-891.  (back)
14. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-1477.  (back)
15. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000; 164: 247-256.  (back)
16. Chao KC, Chao KF, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One 2008; 3: e1451.  (back)
17. Păunescu V, Deak E, Herman D, Siska IR, Tănasie G, Bunu C, et al. In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med 2007; 11: 502-508.  (back)
18. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004; 94: 678-685.  (back)
19. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109: 1292-1298.  (back)
20. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 2008; 3: e1886.  (back)
21. Zhao S, Wehner R, Bornhäuser M, Wassmuth R, Bachmann M, Schmitz M. Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells Dev 2010; 19: 607-614.  (back)
22. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 1995; 16(4): 557-564.  (back)
23. Wu T, Bai H, Wang CB, Zhang Q, Tantai LF, Wang XJ, et al. Autologous bone marrow-derived mesenchymal stem cells and peripheral blood stem cells cotransplantation in treatment of hematological malignant diseases. Zhong hua Nei Ke Za Zhi 2009; 48(5): 392-395.  (back)
24. Zhang X, Li JY, Cao K, Lu H, Hong M, Qian S, et al. Cotransplantation of HLA-identical mesenchymal stem cells and hematopoietic stem cells in Chinese patients with hematologic diseases. Int J Lab Hematol 2010; 32(2): 256-264.  (back)
25. Liu K, Chen Y, Zeng Y, Xu L, Liu D, Chen H, et al. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study. Stem Cells Dev 2011; 20(10): 1679-1685.  (back)
26. Zhao ZG, Liang Y, Li K, Li WM, Li QB, Chen ZC, et al. Phenotypic and functional comparison of mesenchymal stem cells derived from the bone marrow of normal adults and patients with hematologic malignant diseases. Stem Cells Dev 2007; 16: 637-648.  (back)
27. Chao YH, Peng CT, Harn HJ, Chan CK, Wu KH. Poor potential of proliferation and differentiation in bone marrow mesenchymal stem cells derived from children with severe aplastic anemia. Ann Hematol 2010; 89: 715-723.  (back)
28. Wu X, Li Y, Zhu K, Wang Z, Chen S, Yang L. GATA-1, -2 and -3 genes expression in bone marrow microenviroment with chronic aplastic anemia. Hematology 2007; 12: 331-335.  (back)
29. Chen SL, Fang WW, Qian J, Ye F, Liu YH, Shan SJ, et al. Improvement of cardiac function after transplantation of autologous bone marrowmesenchymal stem cells in patients with acute myocardial infarction. Chin Med J (Engl) 2004; 117(10): 1443-1448.  (back)
30. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004; 94(1): 92-95.  (back)
31. Wang JA, Xie XJ, He H, Sun Y, Jiang J, Luo RH, et al. [A prospective, randomized, controlled trial of autologous mesenchymal stem cells transplantation for dilated cardiomyopathy]. Zhonghua Xin Xue Guan Bing Za Zhi 2006; 34(2): 107-110.  (back)
32. Chen S, Liu Z, Tian N, Zhang J, Yei F, Duan B, et al. Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol 2006; 18(11): 552-556.  (back)
33. Yang Z, Zhang F, Ma W, Chen B, Zhou F, Xu Z, et al. A novel approach to transplanting bone marrow stem cells to repair human myocardial infarction: delivery via a noninfarct-relative artery. Cardiovasc Ther 2010; 28(6): 380-385.  (back)
34. Wang JA, Xie XJ, He H, Sun Y, Jiang J, Luo RH, et al. [A prospective, randomized, controlled trial of autologous mesenchymal stem cells transplantation for dilated cardiomyopathy]. Zhonghua Xin Xue Guan Bing Za Zhi 2006; 34(2): 107-110.  (back)
35. Zhang ZX, Guan LX, Zhang K, Zhang Q, Dai LJ. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy 2008; 10(2): 134-139.  (back)
36. Chen G, Wang Y, Xu Z, Fang F, Xu R, Wang Y, et al. Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. J Transl Med 2013; 11: 21.  (back)
37. Jin JL, Liu Z, Lu ZJ, Guan DN, Wang C, Chen ZB, et al. Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia. Curr Neurovasc Res 2013; 10(1): 11-20.  (back)
38. Glavaski-Joksimovic A, Bohn MC. Mesenchymal stem cells and neuroregeneration in Parkinson’s disease. Exp Neurol 2013; 247: 25-38.  (back)
39. Li X, Xu WF. China’s efforts to shed its title of “Leader in liver disease”. Drug Discov Ther 2007; 1(2): 84-85.  (back)
40. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al.  Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418(6893): 41-49.  (back)
41. Li JT, Liao ZX, Ping J, Xu D, Wang H. Molecular mechanism of h epatic stellate cell activation and antifibrotic therapeutic strategies. J Gastroenterol 2008; 43: 419-428.  (back)
42. Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol 2012; 27(Suppl 2): 112-120.  (back)
43. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med 2012; 1(10): 725-731.  (back)
44. Zhao D, Cui D, Wang B, Tian F, Guo L, Yang L, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone 2012; 50(1): 325-330.  (back)
45. Gan Y, Dai K, Zhang P, Tang T, Zhu Z, Lu J. The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion. Biomaterials 2008; 29(29): 3973-3982.  (back)
46. Chen D, Zhang X, He Y, Lu J, Shen H, Jiang Y, et al. Co-culturing mesenchymal stem cells from bone marrow and periosteum enhances osteogenesis and neovascularization of tissue-engineered bone. J Tissue Eng Regen Med 2012; 6(10): 822-832.  (back)
47. Jiang R, Han Z, Zhuo G, Qu X, Li X, Wang X, et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011; 5(1): 94-100.  (back)
48. Hu J, Yu X, Wang Z, Wang F, Wang L, Gao H, et al. Long term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Endocr J 2013; 60(3): 347-357.  (back)
49. Wan J, Xia L, Liang W, Liu Y, CaiQ. Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats. J Diabetes Res 2013; 2013: 647107.  (back)
50. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011; 92(1): 26-36.  (back)
51. Fu X, Qu Z, Sheng Z. Potentiality of mesenchymal stem cells in regeneration of sweat glands. J Surg Res 2006; 136: 204-208.  (back)
52. Tao R, Sun TJ, Han YQ, Xu G, Liu J, Han YF. Epimorphin-induced differentiation of human umbilical cord mesenchymal stem cells into sweat gland cells. Eur Rev Med Pharmacol Sci 2014; 18: 1404-1401.  (back)
53. Tao R, Sun TJ, Han YQ, Xu G, Liu J, Han YF. Epimorphin-induced differentiation of human umbilical cord mesenchymal stem cells into sweat gland cells. Eur Rev Med Pharmacol Sci 2014; 18: 1404-1401.  (back)
54. Tao R, Sun TJ, Han YQ, Xu G, Liu J, Han YF. Epimorphin-induced differentiation of human umbilical cord mesenchymal stem cells into sweat gland cells. Eur Rev Med Pharmacol Sci 2014; 18: 1404-1401.  (back)
55. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 2010; 45(12): 1732-1740.  (back)
56. Fang B, Song Y, Liao L, Zhang Y, Zhao RC. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 2007; 39: 3358-3362.  (back)
57. Fang B, Song YP, Liao LM, Han Q, Zhao RC. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 38: 389-390.  (back)
58. Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, et al. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant 2007; 11(7): 814-817.  (back)
59. Fang B, Song Y, Zhao RC, Han Q, Cao Y. Treatment of resistant pure red cell aplasia after major ABO-incompatible bone marrow transplantation with human adipose tissue-derived mesenchymal stem cells. Am J Hematol 2007; 82(8): 772-773.  (back)
60. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 2010; 45(12): 1732-1740.  (back)
61. Fang B, Song Y, Liao L, Zhang Y, Zhao RC. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 2007; 39: 3358-3362.  (back)
62. Fang B, Song YP, Liao LM, Han Q, Zhao RC. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 38: 389-390.  (back)
63. Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, et al. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant 2007; 11(7): 814-817.  (back)
64. Fang B, Song Y, Zhao RC, Han Q, Cao Y. Treatment of resistant pure red cell aplasia after major ABO-incompatible bone marrow transplantation with human adipose tissue-derived mesenchymal stem cells. Am J Hematol 2007; 82(8): 772-773.  (back)
65. Fang B, Song Y, Zhao RC, Han Q, Lin Q. Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc 2007; 39(5): 1710-1713.  (back)
66. Pileggi A, Xu X, Tan J, Ricordi C. Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant 2013; 18(6): 672-681.  (back)
67. Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307(11): 1169-1177.  (back)
68. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009; 27: 1421-1432.  (back)
69. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010; 69: 1423-1429.  (back)
70. Wang D, Akiyama K, Zhang H, Yamaza T, Li X, Feng X, et al. Double allogenic mesenchymal stem cells transplantations could not enhance therapeutic effect compared with single transplantation in systemic lupus erythematosus. Clin Dev Immunol 2012; 2012: 273291.  (back)
71. Shi D, Liao L, Zhang B, Liu R, Dou X, Li J, et al. Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-κB signaling. Exp Hematol 2011; 39: 214-224.  (back)
72. McMahon, D. and Thorsteinsdottir, H. Lost in translation: China’s struggle to develop appropriate stem cell regulations. Scripted 2010; 7(2): 284-294.  (back)
73. Ricordi C. Towards a constructive debate and collaborative efforts to resolve current challenges in the delivery of novel cell based therapeutic strategies. CellR4 2013; 1(1): 2-7.  (back)
74. Yuan W, Sipp D, Wang ZZ, Deng H, Pei D, Zhou Q, Cheng T. Stem cell science on the rise in China. Cell Stem Cell 2012; 10(1): 12-15.  (back)