Time
2006
Unrelated hematopoietic stem cell transplantation technique
Unrelated hematopoietic stem cell transplantation collection technique
2009
Cord blood stem cell therapy technology (trial)
Tissue-engineering tissue transplantation therapy technique (trial)
2.3 Funding Support and Resources
Multiple sources are funding RM studies and translational application. After 1999, the MST approved the National Program on Key Basic Research Project (973 Program) related to tissue engineering, and the stem cell field had the largest number of “973 Program” projects. Research into the clinical transformation and application of stem cell therapy was established in the biotechnology and medical technology field of the “863 Program”. The National Natural Science Foundation of China (NSFC) funded about 2000 and 2 hundred million RMB Yuan for this study, including 5627 items (Fig. 1a, b). Up to now, about 3 billion RMB from the MST, CAS and NSFC has been invested in this field. Both the amount of funding and number of projects is increasing annually. Other funding for RM from companies is about 5 hundred million RMB. By the end of 2015, China MST approved its first key project in the fields of science and technology was stem cells and their translational application.
Fig. 1
National Natural Science Foundation of China investment in regenerative medicine from 2000 to 2012. a Amount of funding; b Number of funds (Reprint from Biao Cheng, Shuliang Lu and Xiaobing Fu, Regenerative medicine in China: demands, capacity, and regulation. Burns & Trauma 2016. 4:24)
2.4 Translating Outcomes into Industrialization
The establishment of centers and technological translational application are important for RM development. Since 1999, China has established more than 30 RM centers. These centers are involved in stem cell research and its translational application (e.g., national stem cell east centre and national stem cell centers in Tianjin, Qingdao, Wuxi, Taizhou etc.) [6], national stem cell and RM technology innovation strategic alliance (sponsors and governing members include 27 first-class research institutes, well-known three-A hospitals, several “211 Project” key universities and industry leaders) and a tissue-engineering innovation center in Shanghai. In 2011, the first academic workstation for the industrialization of stem cell technology was launched in the Inner Mongolia Autonomous Region. Companies such as Cyagen Biosciences (Guangzhou) and Hangzhou Biowish Technology (Biowish) are specialized in the development and sales of stem cell products. In 2009, NeoStem announced that it had reached an exclusive agreement for strengthening biomedical cooperation with Shanghai enterprises. This agreement aims to establish a network of stem-cell collection and treatment centers in Shanghai, Jiangsu, Zhejiang, Fujian, Anhui and Jiangxi provinces. In 2010, the Beike Stem Cell Bank and Stem Cell Preparation Laboratory successfully passed the ISO9001 quality management system certification and obtained the qualification certification issued by China Quality Certification Center, becoming the first comprehensive stem cell bank to pass ISO9001 quality management system certification in China [7].
3 Major Progress in RM in China
Since 2002, major foreign media paying attention to the progress of RM in China included the Wall Street Journal, New Scientist and Times, and Journal of Applied Behavioral Analysis [8, 9]. In 2009, more articles were published in Nature and the subjournal Nature Reviews Molecular Cell Biology [10, 11], Cell and subjournal Cell Stem Cell [12], New England Journal of Medicine [13], and Regenerative Medicine and Science [14–16]. The media has noted the significant progress in China and interpreted China’s policies on stem cells, tissue engineering and related areas. It noted that the Chinese government has invested a large amount of funding in RM represented by stem cell study, tissue engineering and clinical translational studies and the country has made great progress. The reports indicated that the Chinese government will enhance investment in RM and has been active in recruiting well-trained researchers in the 21st century and that China is leading the area in some aspects. However, China still faces challenges in regulation, governance and management.
3.1 Stem Cells
3.1.1 Overview
Chinese researchers started to pay attention to stem cells during the 1980s. In China, it is prohibited to conduct reproductive cloning, utilize a human embryo beyond day 14, fuse human and non-human gametes and implant research embryos into a human or animal uterus. The government has greatly invested in stem cell research concentrated in several key labs in Beijing and Shanghai. In 2001, the CAS established a key lab of stem cell biology, which was followed by the establishment of a stem cell research network composed of the Shanghai Life Science Institute of CAS, Guangzhou Institutes of Biomedicine and Health, Biology Physics Institute, Zoology Institute, Genetics and Development Institute and Kunming Zoology Institute (Fig. 2). Other famous universities and institutes have established stem cell institutes or centers with or without international cooperation (Table 2). Many papers and monographs on stem cells and RM have been published (Tables 3 and 4). Thus, China is close to the global advanced-research level of embryo stem cells and other stem cells.
Fig. 2
Major Research Institutions for Stem Cell Research in China. (1) Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Partners are Shanghai Jiaotong University School of Medicine, Shanghai Xinhua Hospital, Changzhou City First People’s Hospital, The Third Hospital Affiliated to Suzhou University, established a biomedical translational research base. The research focuses on establishing embryonic stem cell lines, isolating tissue stem cells, studying their stemness and differentiation induction, and stem cell immunology. The main focus is on regulating the differentiation of stem cells, aiming to solve several major problems in the clinical application of stem cells and developing protocols to derive iPS to further understand their roles in disease development. (2) Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences—South China Institute for Stem Cell Biology and Regenerative Medicine, Key Laboratory of Regenerative Biology. This is first international demonstrative base of technology collaboration. Guangdong International Technology Collaboration Demonstrative Base of Stem Cell and Regenerative Medicine. Cooperation institutions are Korea Stem Cell Research Center/YonSei University College of Medicine, Faculty of Medicine, and the Chinese University of Hong Kong. Research Areas are chemical biology for stem cell, stem cell physiology, therapeutic, differentiation, molecular diagnoses and self renew the mechanism of induced pluripotent stem cell and its clinical application. (3) The Institute of Biophysics, Chinese Academy of Sciences. Research areas are biology of embryonic stem cell, pluripotent stem cells (PSCs), the function and regulation of neural stem cells in the mammalian brains; Institute of Zoology, Chinese Academy of Sciences—The Research Center of Stem Cells and Regenerative Medicine. The Chinese-French Laboratory of Biology of Embryonic Cells of Mammalians (LABIOCEM) combined with the French National Institute for Agricultural Research focusing on stem cells and iPS cells of domestic animals, the mechanisms of cloning and therapeutic cloning, which markedly improved the efficiency of animal cloning; The Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences and Nanjing Drum Tower Hospital the affiliated hospital of Nanjing University Medical School established the Nanjing Stem Cells and Biomaterials Research Center, focused on stem cell 3D culture and self-renewal regulatory network, stem cell and biomedical materials, tissue regeneration and wound healing and stem cell translational medicine. (4) The Kunming Institute of Zoology, the Chinese Academy of Sciences, cooperation with Yunnan provincial government established the Key Laboratory of Animal Reproductive Biology focused on rhesus monkey embryonic stem cell self-renewal mechanism with primate animal disease models, research stem cell pharmacology, and promoting Chinese clinical stem cell therapy. “Springer publications remain neutral with regard to contested jurisdictional claims in published maps”
Table 2
Main Stem Cell Research Institutes in China
Time | Name | Composition |
|---|---|---|
2001.01 | Peking University Stem Cell Research Center | Peking University |
2013.07 | Peking University Center for Craniofacial Stem Cell Research and Regeneration | |
2001.02 | Union Stem Cell and Gene Engineering | Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College |
2002.01 | Institute of Reproductive and Stem Cell Engineering, Central South University | Central South University |
2004 | National Engineering Research Center of Human Stem Cells | |
2005 | Key Laboratory of Human Stem Cells and Reproductive Engineering | |
2003.01 | Center for Stem Cell Biology and Tissue Engineering Sun Yat-Sen University | Sun Yat-Sen University |
2008.10 | Med-X-Renji Hospital Clinic Stem Cell Research Center | Med-X Research Institute of Shanghai Jiao Tong University, Renji Hospital |
2011.03 | Center of Stem Cells and Regenerative Medicine, Tsinghua University | Tsinghua University |
2012.01 | Research Center of Stem Cell and Developmental Biology, Zhejiang University | Zhejiang University |
2012.04 | Sino-US Research Center of Regenerative and Translational Medicine | Institute for Regenerative Medicine, Wake Forest University, Key Laboratory of Neuroregeneration, Nantong University |
2012.06 | Sino-US Research Center of Stem Cell | Tongji University, California Institute for Regenerative Medicine |
2012.12 | Southern China Center for Stem Cell and Regenerative Medicine | Academy of Military Medical Sciences, Guangdong Provincial Department of science and technology |
Table 3
Main monographs on regenerative medicine published in China
Time | Name | Author | Publishing company |
|---|---|---|---|
2008.03 | Regenerative Medicine: From Basic to Clinic Research | Fu Xiaobing, Wang Zhengguo, Wu Zuze | Shanghai Scientific and Technical Publishers |
2010.05 | Regenerative Medicine: Theory and Technology | Pei Xuetao | Science Press |
2012.03 | Regenerative Medicine | Ding Fei, Liu Wei, Gu Xiaosong | People’s Medical Publishing House |
2013.08 | Regenerative Medicine: Basic and Clinical Research | Fu Xiaobing, Wang Zhengguo, Wu Zuze | People’s Medical Publishing House |
Table 4
Main monographs on stem cells published in China
Time | Name | Author | Publishing company |
|---|---|---|---|
1988.01 | Basic Hematopoietic Stem Cell Transplant | Wu Zuze | People’s Medical Publishing House |
2000.04 | Stem Cells and Developmental Biology | Ye Xinsheng, Xu Tian, Tang Xifang, Pei Xuetao | Military Medical Science Press |
2000.09 | Peripheral Blood Stem Cell Transplantation | Da Wanming, Pei Xuetao | People’s Medical Publishing House |
2000.11 | Hematopoietic Stem Cells Theory and Transplant Technique | Han Zhonchao | Henan Science and Technology Press |
2003.07 | Stem Cell Biology | Pei Xuetao | Science Press |
2005.03 | Stem Cells Theory and Technique | Wang Tinghua, Li Liyan | Science Press |
2005.05 | Stem Cells Biology | Hu Huozhen | Profile of Sichuan University Press |
2006.05 | Principles, Technology and Clinic of Stem Cell | Zhan Chunhua | Chemical Industry Press |
2006.07 | Neural Stem Cell Foundation and Application | Zhu Xiaofeng | Science Press |
2006.12 | Neural Stem Cell | Xu Ruxiang | Military Medical Science Press |
2007.03 | Hematopoietic Stem Cell Biology and Research Methods | Wang Yaping | Science Press |
2007.07 | Stem Cell Aging and Disease | Wang Yaping | Science Press |
2008.02 | Fundamental and Clinic Research of Stem Cells | Yu Yue | Press of University of Science And Technology of China |
2010.07 | New Technologies of Stem Cell Application | Yang Xiaofeng, Zhang Sufen, Guo Zikuan | Military Medical Science Press |
2010.01 | Clinical Research of Mesenchymal Stem Cells | Wang Tong | People’s Medical Publishing House Co., Ltd |
2011.08 | The Basis, Ethics and Principles of Clinical Applications of Stem Cells | Jin Kunlin | Science Press |
2011.12 | Research Legal Regulation of Human Embryonic Stem Cell | Zhao Xu | Shanghai People’s Publishing House |
2012.04 | Mesenchymal Stem Cells: Basic Research and Clinical Application | Han Zhongchao | Science Press |
2012.10 | Clinical Research and Application of Stem Cells | Gu Yongquan, Han Zhongcao, Fu Xiaobing | People’s Medical Publishing House |
2012.10 | Application of Stem Cell Technology for Cardiovascular Diseases | Ma Yitong, Ge Junbo | People’s Medical Publishing House |
2012.06 | Development Report on Technology and Industry of Stem Cell | Dai Tao, Chi Hui, Fu Xiaobing, Pei Xuetao, Zhou Qi, Li Defu, Lan Baoshi | Science Press |
3.1.2 Stem Cell Banks
In 2007, the MST established 4 stem cell banks covering the north, south and east of China. The banks support each other with their own technological advantages and are expected to create a platform for 3 or 4 key technologies of stem cells (Fig. 3) [17]. In 2002, the information network for hematopoietic stem cell donators was released formally online. In 2010, the MH planned to establish 10 hematopoietic stem cell banks.
Fig. 3
Stem Cell Banks in China. (1) Northern Stem Cell Bank and Parthenogenetic hESCs Lines Technology Platform. To establish key technology of clinical-grade human embryonic stem cells and human parthenogenetic embryonic stem cell bank; to create their own stem cells and collect a variety of resources; supply stem cell materials, information, knowledge and technology services; and support for research institutions. (2) Southern Stem Cell Bank and Diseases Stem Cell Lines Technology Platform. To establish disease stem cell lines and hpESC lines, and parthenogenetic technology platform in hESC lines, complete common stem cell culture technique and operating instruction. (3) Chinese Academy of Sciences, Stem Cell Bank and Stem Cell Gene Manipulation Technology Platform. To establish, collect, identify, store and provide stem cells and relevant technique and materials, and improve China stem cell resources (especially human embryonic stem cells), and promote China stem cell research and international academic exchange. (4) Eastern China Stem Cell Bank and Clinical Grade hESC Lines Technology Platform. To take charge of the National Stem Cell bank websites and databases and stem cell bank management and coordination. To establish clinical-grade stem cell lines and non-animal ingredients hESC lines, offer a variety of standardized stem cells, and provide stem cell technical consultation and training. “Springer publications remain neutral with regard to contested jurisdictional claims in published maps”
3.1.3 Basic Stem Cell Studies
Before 2007, basic stem cell studies in China concentrated on bone-marrow and embryo stem cells [18]. Then, China was gradually moving toward the top position in basic stem cell research. In 2001, Fu reported that epidemial cells could be induced into eipdemial stem cells with growth factors in wound healing [19]. Hongkui Deng et al. reported the first inducible pluripotent stem (iPS) cell line from rhesus monkey in Cell Stem Cell [20]. In 2009, Wu et al. first isolated reproductive stem cells and cultured reproductive stem cell strains capable of long-term self-renewal [21]. Zhou and colleagues first cultivated a mouse by using iPS cells [22]. This was the first proof of the totipotency of iPS cells. This finding was elected by Times as one of the Global Top 10 Biomedicine Advances. The journal believed that “this study is a symbol of a major step forward of stem cell research”. In early 2010, Pei and associates increased the iPS induction efficiency by 10-fold by adding vitamin C [23]. The Proceedings of the National Academy of Science USA published the finding of the new function of the stem cell factor receptor C-KIT and application in translational medicine [24]. Chinese researchers published their success in creating cell lines from androgenetic haploid embryonic stem cells, a breakthrough in embryo stem cell research [25]. In 2013, Deng and colleagues used a small molecular compound to induce the reprogramming of somatic cells into multipotent stem cells [26]. In 2013, Cell published a special “Spotlight on China” edition that highlighted the rapid development of immunology study in China and in particular, positively commented on the immunology aspects of applying stem cells for clinical treatment [27, 28].
3.1.4 Therapeutic Applications
The practice of stem cell clinical trials or treatment in China dates back to bone-marrow transplantation in the 1960s, really the transplantation of stem cells in bone marrow. China declared the legality of stem cell treatment as a medical technique following the United Kingdom and the United States.
For therapeutic applications, Zhu and colleagues treated a woman who had chopsticks inserted into her brain from the eyes, which resulted in frontal cerebral-cortex injury. The authors cultivated the brain tissue attached to the chopsticks and were interested in stem cell–motivated self-repair [29]. In 2009, Fu and colleagues regenerated sweat gland s by using bone-marrow mesenchymal stem cells (MSCs). This technology has been applied in more than 30 cases with follow-up for more than 4 years [30]. In 2013, umbilical-cord MSC transplantation was performed in patients with post-traumatic brain syndrome. A total of 40 patients with post-traumatic brain syndrome were randomized to receive stem cell or control treatment. Umbilical-cord MSC transplantation improved the neurological function of the patients. However, these results need to be confirmed by prospective, randomized, multi-center, large clinical studies [31]. At the website of the SFDA (date of search: 2013-08-01), a few stem cell–related products have been approved for clinical trials (Table 5).
Table 5
Stem cells products approved for clinic pre-clinic trial by the SFDA
Accept no. | Generic name | Usage | Date | Unit | Status |
|---|---|---|---|---|---|
X0400586 | Bone marrow mesenchymal stem cells | Injection | 2004.02 | The Foundation of the Chinese Academy of Sciences Institute of Medicine | Approved |
CSL20020071 | Human recombinant stem cell factor for injection | Injection | 2003.05 | The Second Military Medical University | Approved |
X0408234 | Mesenchymal stem cells in myocardial infarction for injection | Injection | 2005.01 | Beijing Yuanhefa Biotechnology | Approved |
X0407487 | Autologous bone marrow mesenchymal stem cells for injection | Injection | 2004.12 | Institute of Transfusion Medicine, Academy of Military Medical Science of PLA | Approved |
CSL01037 | Recombinant stem cell factor for injection | Injection | 2001.09 | Institute of Transfusion Medicine, Academy of Military Medical Science of PLA | Approved |
X0404120 | Umbilical cord blood nuclear progenitor cell for injection | Injection | 2004.07 | Institute of Transfusion Medicine, Academy of Military Medical Science of PLA | Approved |
X0404119
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