What are the challenges in the clinical application of neural stem cell transplantation?

  For neural stem cells to truly function they must go through several stages: reaching the target site (migration), survival, directed proliferation, establishing synaptic connections to establishing effective synaptic connections (functioning). At present, it can be said that there are not small difficulties in each stage, and some of them have achieved certain effect in animal experiments, but in human body is not the same thing at all.  1. Although embryonic stem cells and neural stem cells can be differentiated into neuronal cells in in vitro culture, the percentage of differentiation into functional neurons is not high, about 20-30%, and there is a certain degree of difference in each artificially induced differentiation, so that the output cells cannot be completely homogeneous, and the current production of neural stem cells is about 1010/L, and only 5 ml can be used each time, which cannot be controlled in vivo The number of neurons that can be transformed into neurons in an environment that cannot be controlled in vivo is unknown, not to mention that they have to migrate to become neurons with motor function at specific sites.  2, the synapses of specific neurons will only grow and connect to specific cells of specific “target” tissues, even under optimal laboratory conditions, the growth rate will not exceed 1 mm per day, that is, it may take a long time before it is possible to form neurons and “target cells This means that it may take a long time to form connections between neurons and “target cells”, and more importantly, the problem of directed neuronal connections has not been solved at all yet.  3. The efficacy observed in previously conducted transplantation experiments, and even clinical trials, has not provided a convincing experimental basis or material foundation. At the same time, many of the clinical trials that have been conducted have not been rigorously controlled studies, and no long-term efficacy has been found to provide direct evidence for the reliability of cell transplantation therapy.  4. The existence of tumorigenicity of stem cells is an international consensus and research focus. The Stem Cell Center of Peking University has confirmed that neural stem cells with relatively high maturity also have high tumorigenicity after transplantation. Research at Xuanwu Hospital has shown that cells differentiated from embryonic stem cells are highly tumorigenic after transplantation while exerting therapeutic effects. Theoretically, as long as cells with the ability to divide and proliferate are implanted in animals, they have the potential to form tumors. Is it possible that a small number of cell transplants do not grow tumors but may have therapeutic effects? There is no uniform understanding of how much transplantation is appropriate. What are the cells that directly produce tumors? What are the characteristics of these cells? How to ensure the differentiation potential of stem cells while suppressing their excessive proliferation? These and other questions need to be addressed by scientists in depth. Therefore, only through meticulous preclinical large animal (monkey) testing can we enter a new era of widespread clinical application of stem cell technology.  5. There is still a long road to achieve between establishing synaptic connections and establishing effective synaptic connections (to function). Laboratories have found that neural stem cells can send several synaptic connections to injured neural tissue, but if these synaptic connections cannot assume meaningful function, the outcome is still unclear. This is a consequence of the general lack of long-term efficacy observation in current clinical studies of neural stem cell transplantation.  6. Even short-term efficacy of neural stem cell transplantation clinical studies is questionable. For example, some studies have shown that neural stem cell transplantation in cerebral palsy patients can improve the spasticity of the patients. What exactly is the rationale for the relief of spasticity? What is the laboratory basis for this? To what extent did the spasticity of the patients improve? Do the results stand up to a randomized controlled blinded test? We know that sometimes the patient’s psychological state can also affect the patient’s spasticity ……7, and there is a lack of observation of long-term efficacy.  In conclusion, neural stem cell transplantation is still a very immature therapeutic technique in clinical practice. The main purpose of its clinical application is to study the feasibility of the technology and the observation of its efficacy, which should be carried out by strictly selecting patients, using scientific research methods, focusing on research, and suitable to be carried out in research institutions with strong technical strength (combined with clinical). This requires the health authorities to strengthen supervision and management and to implement a technical access system. It is worthwhile for patients to be alerted to the fact that some hospitals are currently using stem cell transplantation as a “gimmick”, exaggerating the therapeutic effects of stem cell transplantation, and even developing it as a fee-based program.