Source: Special issue of Stem Cell and Regenerative Medicine, Medical Reference News

Overview: Stem cells are a kind of primitive cells with self-differentiation ability and organ repair function, and are an important cell resource, which has certain research value and clinical application prospect. Stem cells and their derived tissues and organs are expected to be applied in clinical practice, forming a new therapeutic means or "drugs", stem cell therapy will produce new breakthroughs in the traditional medical industry in the next 5 to 10 years, and will also promote the transformation of the modern pharmaceutical industry, while producing a large number of emerging markets. How to correctly understand the national policy, carry out stem cell clinical research legally, and promote the development of stem cell industry is an important topic worthy of attention. In this paper, the concept and development status of stem cells are analyzed, the practice and results of exploring stem cells in hospitals in recent years are described, and the future development prospect of stem cells is prospected.

一、the concept and connotation of stem cells

Stem cells are primitive and unspecialized cells with self-renewal and multidirectional differentiation potential. On the one hand, they can obtain more stem cells through self-renewal, and on the other hand, they can differentiate into some specialized cells under certain conditions. Hematopoietic stem cells, known to the public as adult stem cells, have been in clinical use for more than half a century, saving the lives of hundreds of thousands of patients. Stem cell is an important cell resource, which has research value and clinical application prospect. Stem cells and their derived tissues and organs can be applied in clinic to form a new therapeutic means or "drugs", and promote the development and industrialization of regenerative medicine and alternative medicine, which is of great significance to improve the quality of human life. The use of stem cells to repair or replace damaged cells will become one of the effective means to overcome human diseases, and stem cell therapy technology has broad prospects for human refractory diseases.

二、the development status of stem cells in China

With the support of national science and technology projects such as 973 Plan, 863 Plan, National Science and Natural Foundation and national major science and technology projects, especially under the guidance of the stem cell pilot project of the Chinese Academy of Sciences, the basic research and technology construction of stem cells in China has made great and rapid progress. The project team supported by the National Key Research and Development Program "Stem Cell and Translational Research" from 2016 to 2017 has published more than 40 articles in the international top academic journals "Nature" and "Cell" and its series of sub-journals. However, since the State Food and Drug Administration issued the first clinical trial approval of stem cell drugs in 2004, the three stem cell products approved by the CFDA before 2005 are not approved for market today. Due to the lack of norms and ethical restrictions, China's stem cell clinical research has been stagnant, stem cell transformation far behind foreign countries.

In this context, in July 2015, the State Health Science and Education Fa [2015]48 "Stem Cell Clinical research Management Measures (Trial)" (hereinafter referred to as the "management Measures") and the State Health Office Science and education Fa [2015]46 "Stem cell preparation quality Control and preclinical research Guiding Principles (trial)" (hereinafter referred to as the "Guiding Principles") two documents were officially issued. The "Administrative Measures" have strict regulations on the medical institutions that carry out stem cell clinical research, including third-class A hospitals, which have the corresponding diagnosis and treatment subjects with the stem cell clinical research; Obtain the qualification of relevant professional drug clinical trial institutions according to law. At present, the first batch of stem cell clinical research institutions registered by the national Health and Family Planning Commission and the Food and Drug Administration have a total of 102, and only 8 projects declared by 7 institutions have completed the filing of stem cell clinical research projects. Among them, the cell types include embryonic stem cells, mesenchymal stem cells, neural stem cells, lung stem cells and other cell types with different differentiation potential. Indications include acute myocardial infarction, pediatric cerebral palsy, psoriasis, premature ovarian failure with infertility, Parkinson's disease, lung disease, knee osteoarthritis and macular degeneration.

At the beginning of the establishment of Shanghai East Hospital, the hospital brand, talent team and research foundation were weak. In recent years, the hospital has formed a certain foundation in the field of scientific research transformation through the close combination of scientific research and clinical research. In order to build the characteristics of the hospital, Shanghai Oriental Hospital has laid out the stem cell industry in a forward-looking way. Taking advantage of its location in Zhangjiang National Independent Innovation Demonstration Zone and China (Shanghai) Pilot Free Trade Zone, the hospital has taken the lead in the practice and exploration of stem cell transformation over the years, and has become the core base of stem cell transformation in East China. Through the practice of stem cell transformation, the curve overtaking is realized. This paper briefly expounds the exploration of stem cell field in Shanghai Oriental Hospital.

三、Dongfang Hospital to explore a new model of stem cell industry

Build a transformation platform

To develop the stem cell industry, there must be a physical foundation. In 2013, Dongfang Hospital laid out the development of the stem cell industry in advance, and established a stem cell industry base covering three service platforms: stem cell preparation and quality inspection service platform, stem cell technology product pilot platform, and stem cell industry promotion service platform. The whole industry chain of stem cell preparation, preclinical research, clinical research, achievement specialty, and industrial promotion has been formed. The base has completed the construction of 8,000 square meters of site, established stem cell collection, separation, sorting, purification, expansion, culture, storage system in line with international quality control standards, and established a quality management SOP system, including laboratory personnel, training, instruments, consumables, quality control and other management systems. The laboratory environment monitoring and testing system has been established, with large animal operating rooms, a variety of disease-related animal models and behavioral analysis systems, which can provide a unified clinical-level standard cell preparation and preclinical research platform for stem cell projects with promising transformation prospects. The construction of a stem cell resource bank based on the concept of seed bank (mother bank), main bank (expansion bank), working bank (application bank), product bank, and third-party cell bank can provide universities, scientific research institutes, enterprises and institutions with cell sources to meet the needs of scientific research, clinical and drug screening. The Institute of Regenerative Medicine was established in cooperation with the College of Life Science and Technology of Tongji University to focus on the common problems and key scientific issues arising from stem cell clinical practice.

In the connotation construction. The platform has established a complete stem cell clinical research institution and a safety and effectiveness evaluation system for stem cell technology products, including stem cell quality evaluation standards, testing equipment and facilities, and stem cell clinical research project initiation procedures; The Academic Committee for Stem cell clinical Research and the Ethics Committee for Human cell Clinical Research have been established, with a complete team of experts and work system. The application flow chart of clinical research projects has been formulated, and all clinical research projects should be designed and checked by statistical experts before being formally submitted to the hospital Ethics Committee. All clinical research projects should be reviewed and evaluated in accordance with the requirements of management measures, and can be formally implemented after ethical review.

Innovative management mode

Dongfang Hospital adopts the Center director responsibility system under the leadership of the Board of Directors. The board of directors is the decision-making body of the center. The director of the office of the Center is responsible for the daily operation of the center, and the expert advisory Steering Committee, academic committee and ethics Committee are also set up. The five-member board of directors is mainly responsible for co-opting and by-electing directors, approving the development plan and work plan of the base, formulating and revising the constitution of the base, and deciding other major matters; The expert committee composed of 21 people is mainly responsible for macro-review of the scientific research and development direction of the base, and guide the development plan of the base; The 15-member Stem Cell Clinical Research Academic Committee is responsible for the scientific review of stem cell clinical research projects and the evaluation of stem cell technology; The 11-member Human Cell Clinical Research Ethics Committee is responsible for the ethical review of stem cell clinical research; In addition, a special stem cell base office was set up to organize and supervise the implementation of the project.

Innovate the talent introduction mechanism

Talent is fundamental to the rapid development of the East in recent years. Dongfang Hospital adopts occupational diversification in the introduction of talents, insisting that talents may not be owned by us, but we must adhere to the principle of being used for us, and cooperate with the Shanghai Institute for Advanced Study of the Chinese Academy of Sciences, outstanding state-owned enterprises and private enterprises scientific research backbone personnel in the stem cell industry to realize the mutual employment and part-time employment of researchers and doctoral supervisors, and establish a new mechanism to promote the sharing of talents and intellectual resources. Through the form of outsourcing of research tasks, we employ experts in the field of stem cells as scientific advisers to the stem cell base. At present, we have more than 200 stem cell talents, including 2 academicians, 5 chief scientists of 973, 5 chief scientists of 863, and 5 chief scientists of National key research and development programs. It is a national innovative research group unit. The staff consists of the stem cell basic research team, the technology research and development team and the clinical research team.

四、Initial achievements of Dongfang Hospital

Form social groups

»Led the establishment of Shanghai Stem Cell Industry Alliance. On June 24, 2013, Dongfang Hospital jointly established the "Shanghai Stem Cell Industry Alliance" with 63 institutions including universities, enterprises and public institutions, and scientific research institutes, as the chairman and Secretary-General unit, and the alliance units have expanded to 80.

»Initiated the establishment of Shanghai's first cross-industry innovation alliance. Based on the stem cell industry base, the Shanghai Smart Medical Industry Innovation Alliance jointly initiated by Oriental Hospital, Shanghai Biomedicine Industry Association, Zhongshan Hospital and nine other units was officially established in Pudong on October 20, 2015.

»As the president unit, he established the Stem Cell Research and Application branch of China Plastic and Aesthetic Association. The branch was established in Boao, Hainan from October 20 to 22, 2017. It aims to unite experts engaged in plastic surgery and stem cell research and application industry across the country, jointly promote and improve the academic level of research and application of stem cells in the field of plastic surgery and beauty, cultivate and standardize industry behavior, safeguard the legitimate rights and interests of practitioners, and expand the application of stem cells in the plastic surgery industry.

Undertake important projects

»Approved stem cell translational medicine industry base project. At the end of December 2014, Dongfang Hospital was approved as the major project of special development fund of Shanghai Zhangjiang National Independent Innovation Demonstration Zone - Stem Cell Translational Medicine Industry Base Project of Shanghai Zhangjiang National Independent Innovation Demonstration Zone (project approval number ZJZX-ZD-201402), with a total investment of 255 million yuan and government investment of 105 million yuan. Hospital matching and social financing of 155 million yuan.

»It was approved as the first batch of "four new" economic innovation bases in Shanghai. In July 2015, with the strong support of Shanghai Municipal Economic and Information Technology Commission and Shanghai Zhangjiang Hi-Tech Industrial Development Zone Management Committee, Dongfang Hospital Stem Cell Translational Medicine Industrial Base, as the only non-enterprise unit in the city, was approved as the first 50 pilot units for the construction of "four new" economic innovation bases in Shanghai.

»Approved the national key research and development plan. As the undertaking unit, Dongfang Hospital was approved for two pilot projects of "Stem Cell and translational Research" of the National Key Research and Development Plan in 2016, namely: (1) Tissue Stem cells and pathological tissue Bank of major diseases related to nervous system and heart; (2) "Research on the mechanism of islet cell transdifferentiation and regeneration in Diabetes Mellitus by using Microenvironment in vivo", with a total funding of 36 million yuan. In 2017, three key projects of the national key research and development Plan "Stem cell and Transformation Research" were approved, respectively: "Stem cell treatment of heart failure", "Research on the regulatory mechanism of bone marrow mesenchymal stem cells and their interaction with hematopoietic stem cells", and "genetic and epigenetic regulation of stem cell aging", with a total funding of 51.06 million yuan.

Promote clinical research

»The first institutions to be registered by the National Stem Cell Clinical research Institute. On December 8, 2015, the National Health and Family Planning Commission required institutions conducting stem cell clinical research to submit an application for institutional filing in accordance with the provisions of the "Management Measures". There are a total of 12 institutions in Shanghai that have submitted applications for institutional filing. On October 24, 2016, the first batch of hospitals registered by stem cell clinical research institutions, a total of 30 hospitals in 16 provinces and cities, Shanghai East Hospital ranked among them.

»The first institutions to complete the national stem cell clinical research project record. On November 28, 2016, in accordance with the requirements of the "Management Measures", Dongfang Hospital has formally submitted to the Shanghai Municipal Health and Family Planning Commission the "Clinical research of human umbilical cord mesenchymal stem cells for the treatment of heart failure" and "Clinical research of Human autologous bronchial basal layer cells for the treatment of mesenchymal lung Disease" stem cell clinical research project records written materials. On March 16, 2017, the Medical Research registration and filing information system publicized the first 6 projects (later increased to 8 projects) that completed the national stem cell clinical research project, and the project of "Clinical research of human autologous bronchial basal layer cells for the treatment of mesenchymal lung disease" filed by Dongfang Hospital completed the filing. On September 4, 2017, two new projects of stem cell clinical research record project were submitted to Shanghai Municipal Health and Family Planning Commission, which are currently awaiting domestic review.

Enhance social impact

»Radiate related enterprises in the Yangtze River Delta. Dongfang Hospital actively responds to the call of the state to further promote collaborative innovation and open innovation, build an efficient and powerful common key technology supply system, and strive to achieve major breakthroughs in key technologies. Dongfang Hospital makes full use of its own talents, technology, research and development, capital, management and other advantages of its own stem cell translational medicine industry base to play a radiating role for related stem cell enterprises and institutions in the Yangtze River Delta region. At present, it is or has been actively negotiating with many enterprises and institutions in the stem cell industry, such as Soochow University, Shanghai Lianxiang Life Technology Co., LTD., Shanghai Biang Biopharmaceutical Technology Co., LTD., and reached more than 10 cooperation agreements.

»Take the lead in carrying out extensive international cooperation. Dongfang Hospital has introduced or agreed to introduce cell therapy technology from the University of Geneva in Switzerland, C-Cure® technology from the Mayo Clinic in the United States, adipose-derived stem cell technology from the University of Pittsburgh in the United States, neural stem cell technology from the California Institute for Regenerative Medicine in the United States, and cell membrane technology from Tokyo Women's Medical University in Japan.

 »Participate in major stem cell industry media campaigns. Xinhua News Agency invited manuscripts. In 2016, Xinhua News Agency invited then-President Liu Zhongmin to draft the Current Situation and Trend of Global stem cell Regulation and approval Policies, which was included in the special issue of the financial and economic weekly "Battle Life Energy" for the reference of NPC deputies; CCTV reported. Dongfang Hospital actively responds to the call of the state to further promote collaborative innovation and open innovation, build an efficient and powerful common key technology supply system, and strive to achieve major breakthroughs in key technologies, and makes full use of its own talents, technology, research and development, capital, management and other advantages of its own stem cell translational medicine industry base to play a radiating role in related stem cell enterprises and institutions in the Yangtze River Delta region. CCTV News Broadcast program carried out a special report on this; G20 Summit Special issue. During the G20 Summit, Dongfang Hospital wrote "Saving lives with science", which was used as the front page of China Daily's G20 Summit special issue in Zhangjiang Park for the leaders of the G20 Summit participants' reference.

五、Development and Prospects

On August 8, 2016, the "13th Five-Year Plan for National Science and Technology Innovation" was released, and stem cell and regenerative medicine, as a new biomedical technology, were emphasized to have innovative breakthroughs and application development, in order to promote the transformation and application of technology and serve the national economic and social development, and greatly improve the international competitiveness of bioeconomy. On October 25, 2016, the full text of the "Healthy China 2030" plan was published, proposing that "stem cells and regenerative medicine" as a major scientific and technological project was included in the planning outline, aiming to promote the progress of medical science and technology and promote health science and technology innovation. On November 7, 2016, the six departments of the Ministry of Industry and Information Technology, the National Development and Reform Commission, the Ministry of Science and Technology, the Ministry of Commerce, the Health and Family Planning Commission, and the Food and Drug Administration jointly issued the "Guidelines for the Development of pharmaceutical industry Development Planning", clearly supporting the development of new medical technologies such as stem cell therapy, focusing on promoting cell therapy products such as stem cells and immune cells, and vigorously developing cell therapy product preparation technology. Beijing, Shanghai, Guangzhou, Shenzhen, Hebei and Yunnan have taken the development of stem cells and regenerative medicine as an important direction of future development and actively introduced supporting policies. However, these policies are still oriented, and there are still many constraints on the development of the stem cell industry, and it is urgent to accelerate the introduction of China's stem cell production and preparation standards and norms as soon as possible.

In order to realize the industrialization of stem cells, we must vigorously accelerate clinical research, and still need to be driven by implementation rules. At present, the lack of national strategic stem cell resource bank that can provide unified standard cell source and the lack of multi-center stem cell clinical research platform that conforms to international standards are one of the main reasons that hinder the industrialization of stem cells in China. Led by the government, regional integration of stem cell clinical research resources, the creation of a multi-center clinical research collaborative network, the construction of a stem cell preparation platform, stem cell quality control and quality inspection platform that can scale production and provide standardized cell sources for the whole country, and the implementation of pilot trials under the premise of following scientific norms, ethical norms and technical norms. It is one of the possible development directions in the future to conduct clinical research directly on projects that have been validated in previous studies through ethics, safety and effectiveness. With the further liberalization of stem cell policy, it is hoped that the summary of the practice and exploration of Shanghai Dongfang Hospital in the field of stem cells in this paper can provide certain references for other institutions to build stem cell platforms and develop stem cell industry.