Data show that there are about 8.9 million patients with heart failure in China, and nearly half of the patients die within 5 years after the diagnosis of heart failure, and their 5-year survival rate is lower than that of most malignant tumors. In the past, heart failure could not be cured, and medical means can only delay the development of the disease. In recent years, with the progress of science and technology, patients with heart failure have ushered in new treatments.
In May 2020, Nature reported that two patients with end-stage heart failure were treated with reprogrammed stem cell-based heart failure in China and were discharged from hospital after one year. The patient was injected with cardiomyocytes derived from iPSC differentiation in May 2019, the first known clinical use of iPSC technology in the world to treat damaged hearts. The iPSC (induced pluripotent stem cells), or induced pluripotent stem cells, is a class of pluripotent stem cells cultured by reverse differentiation through artificial reprogramming of somatic cells. With multidirectional differentiation and strong self-replicative potential, iPSC can differentiate into a variety of functional cells under certain conditions, and can cultivate millions or even billions of clinically relevant phenotype cells in vitro.
By acquiring somatic cells (such as fibroblasts), in vitro reprogramming to induce into iPSC, and then derived into target cells (such as cardiomyocytes), and then transplanted into the patient, to achieve the effect of achieving tissue repair and enhancing immunity. In 2006, Professor Shini Yamanaka, Kyoto University, Japan, used a combination of four transcription factors (Oct4, Sox 2, Klf 4 and c-Myc) into mouse skin cells and successfully induced iPSC. As a result, Yamanaka won the 2012 Nobel Prize in Physiology or Medicine six years later. Then, the large-scale research on iPSC was fully launched globally.
At present, iPSC has been used in the clinical treatment of diseases, with indications including heart failure, stroke, knee osteoarthritis, Parkinson's disease, leukemia and so on. In April 2022, China first approved an iPSC-derived cell therapy product for a clinical trial. In addition, iPSC can also be used for drug screening CRO (R & D outsourcing) services for pharmaceutical companies, and for establishing disease models in scientific research companies.
In the era of cell therapy, the iPSC is either the optimal solution
In 2015, the famous cancer doctor and writer Siddhardom mukheri mentioned in his speech "Forget the Pill, Cell Therapy is Coming" that drug therapy had brought a great change to human history, curing diseases such as pneumonia, syphilis, tuberculosis and so on. The model for drug therapy is the —— "disease, drug, target". For example, if you are infected with pneumonia, you can take penicillin to kill the microorganisms. However, models of medication for diseases do not always work. Nature provides another perspective on disease: cells combine into organs, and organs converge into life, and eventually build a rich ecosystem. Mukherjee believes that for a large number of non-infectious diseases, including chronic degenerative diseases including diabetes, hypertension and heart disease, people may have to do "culture something" rather than "kill something", namely cells. The model of cell therapy is: "the cell, the tissue, the environment". Cell therapy will become one of the important ways of disease treatment in the future, which has a unique mechanism of action. The main advantages are: significant and lasting efficacy, personalized therapy, and no diseases that can be treated in traditional drug treatment. It is generally believed that cell therapy includes immune cell therapy, stem cell therapy, and other cell therapies.
In cell families, stem cells are the builders and repair, and immune cells are the defense forces, which cooperate to create the goal of a healthy body. When the human body is still growing, stem cells increase the type and number of cells by dividing and dividing. After the body no longer grows, stem cells can replace and renew the aged or damaged cells in time; When foreign enemies (such as bacteria and viruses) invade or internal rebellious molecules (such as normal cells mutated into cancer cells), immune cells will quickly identify and remove them. In terms of stem cells, they can be divided into embryonic stem cells, perinatal stem cells and adult stem cells by source.
Eyo stem cells are stem cells isolated from embryos;
Perinatal stem cells are stem cells extracted from the umbilical cord blood, umbilical cord, placenta and other tissues attached to the fetus at birth;
Adult stem cells are stem cells derived from adult body tissues, such as bone marrow, fat, nerves, skin, etc.
In the words of one scientist, " adult stem cells are like the trunk of a tree, and embryonic stem cells are like the roots of a tree. Embryonic stem cells not only maintain the characteristics of infinite self-renewal, but also can differentiate into various tissue cell types in the body, which are considered to be the most clinically valuable 'universal cells'."However, because embryonic stem cells need to be extracted from embryos, they have ethical risks in clinical application. And iPSC has the differentiation potential similar to embryonic stem cells, and can be induced by adult somatic cells, which solves the ethical problems faced by regenerative medicine for a long time and the rejection reaction generated by allogeneic transplantation. It has a convenient source, has the ability of universal and personalized therapeutic products, and has a broader application prospect.
The iPSC can also differentiate into immune cells. At present, human iPSC derived CAR (chimeric antigen receptor) -T-K, CAR-NK, CAR-M and other cell therapies have been available and gradually begun to clinical transformation. One milestone was that in October 2020, a team from Chiba University and the Institute of Richard Chemistry in Japan announced that they had successfully completed the world's first transplant of NKT cells based on iPSC differentiation into a cancer patient. It is also the first Japanese attempt to use iPSC to treat tumors. At present, the clinical application of immune cell therapy products are basically using patients' autoimmune cells as raw materials. Autologous immune cell therapy products are highly individualized, with limited production scale, difficult quality control, long preparation cycle and rapid disease progression cannot benefit from them. Through iPSC technology, the allogeneic source of "spot type" immune cell therapy products can be prepared to reverse the body injury or disease. The iPSC can also be used to culture the organoids.
The iPSC can be combined with gene editing technologies such as CRISPR to perform precise and targeted gene knockout or knock-in in many cell types, including single base alteration, correct genetic errors within the stem cell genome and add new pathways to personalized medicine. As an emerging technology, iPSC has "linked" immune cell therapy, stem cell therapy, and even organoid culture and gene editing, showing great potential for application. For now, iPSC may be the optimal cell therapy regimen.
In theory, any type of somatic cell is easily reprogrammed, but the iPSC is largely prepared from easily accessible cells (such as cells derived from the skin or blood). Taking the classical four-factor method as an example, the preparation of iPSC mainly involves four steps: the separation of somatic cells and the introduction of construction inducers of culture-mediated vectors, and the screening and identification of iPSC in cell culture.
At present, iPSC super donor banks have been established in many countries and regions, and China also completed the first preparation of a multicapable cell strain induced by a "super donor" in 2018. Similar to the United States, the Chinese population HLA is complex, and its super donor can only cover about 50% of the Chinese population, so it needs to build a personal iPSC database as a future available reserve.
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