Immunocompatible reversible universal pluripotent stem cells and application thereof

Abstract

The invention discloses immunocompatible reversible universal pluripotent stem cells or derivatives thereof. An inducible gene expression system and an expression sequence of at least one immunocompatible molecule are introduced into the genome of the pluripotent stem cells or the derivatives thereof. The immunocompatible molecules are used for regulating and controlling the expression of genes related to immune response in pluripotent stem cells or derivatives of the pluripotent stem cells. The expression of the immunocompatible molecule is regulated and controlled by an inducible gene expression system. According to the technical scheme, the immunocompatibility between the graft and the receptor can be improved, and the antigen presentation capability of graft cells can be reversibly recovered, so that the clinical safety of such universal pluripotent stem cells and derivatives is improved, and the clinical application value of the universal pluripotent stem cells and derivatives isgreatly expanded.

Description

technical field [0001] The invention belongs to the technical field of genetic engineering, and in particular relates to an immune-compatible and reversible universal pluripotent stem cell and its application. Background technique [0002] Stem cells are a type of "seed" cells with the ability to self-renew and differentiate into specific functional somatic cells. They have the potential to regenerate into various tissues and organs and the human body, and play an important role in major biological activities such as immune response, aging, and tumorigenesis. core and irreplaceable role. According to the degree of stem cell characteristics, stem cells are mainly divided into: totipotent stem cells (Totipotent stem cells), pluripotent stem cells (Pluripotent stem cells, PSCs) and adult stem cells (adult stem cells). [0003] Among them, pluripotent stem cells (PSCs) have almost unlimited self-renewal ability and the potential to develop and differentiate into organs, tissues...

AI Technical Summary

Problems solved by technology

However, for this kind of cells, firstly, the types of antigens presented by HLA-I antigens are reduced by more than two-thirds, and the integrity of the antigens that can be presented is greatly and irreversibly reduced. For various tumors, viruses and other disease antigens The presentation is highly biased, and still retains a considerable degree of risk of tumorigenesis and viral infection, and the risk of disease is higher when CIITA is knocked out at the same time; secondly, 12 high-frequency immune types The ethnic differences of HLA-C antigens are very large, and only 70% of them can be accounted for in some areas through our verification and calculation. However, China, India and other populous countries do not yet have authoritative large-sample HLA data. The use of PSCs is still subject to the test of a huge matching gap; third, this method will undergo several repeated gene editing work, and at least two rounds of single-cell isolation and culture for each gene editing, the whole process requires at least six rounds of single-cell isolation and culture. Cell separation and culture, these processes are inevitable and highly probable due to multiple gene editing off-targets or chromatin instability, or various unpredictable mutations in cells due to a large number of single-cell passages and proliferations, which in turn induce various problems such as carcinogenesis and metabolic diseases

It can be seen that this type of immune compatibility program is also an expedient measure in the "transitional period", and there are still many problems that have not been better resolved

[0007] In addition, some people have designed to induce killing of donor tissues and cells after they become diseased by inducing suicide genes. The loss of suitable donor cells, tissues and organs after killing is another big problem

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