Researchers achieve pluripotent stem cell directed differentiation to regenerate the B immune lineage

Recently, Wang Jinyong's research group at the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences published online in Cellular & Molecular Immunology entitled "Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by." Transcription factors research paper, the study for the first time revealed a set of transcription factor combinations that can efficiently induce stem cell differentiation to produce B immune lineage, demonstrating that in the absence of hematopoietic stem cells can be transplanted to rebuild a fully functional humoral immune system, to achieve antigen-specific humoral immune response, and to generate long-term immune memory. This provides theoretical support and technical reference for the development of B cell therapy for the treatment of B cell-related diseases.

B cells are the key cellular components of humoral immunity, including two major taxa: innate immune B1 cells and acquired immune B2 cells (MZ B, FO B). Any kind of B cell deficiency can lead to impaired humoral immunity and even serious infectious diseases. For the treatment of B cell inactivation and insufficiency-related diseases, regenerating B cells is an ideal choice. The development sites of B cells such as bone marrow and spleen have extremely complex microenvironments, and researchers have tried a variety of methods to regenerate B cells in vitro for many years, but they have been stagnant because they cannot mimic the above complex B cell development microenvironment. The research team expressed three transcription factors of Runx1, Hoxa9 and Lhx2 in multi-potential stem cells (PSCs), and produced hematopoietic seeds by continuous action in the hematopoietic genesis and B lymphogenesis stages, and after transplantation, the in vivo microenvironment of B cell congenital deletion mice was cleverly used to successfully induce a complete and mature B cell lineage in mice.

The team achieved B cell regeneration based on the two-step strategy of "regenerating seed cells in vitro and developing mature in vivo". This induced B cell lineage can detect corresponding B progenitor cells, immature B cells, and mature B cell populations, including pro-B cells, pre-B cells, B1 cells, B2 cells, etc. in multi-organ tissues such as peripheral blood, spleen, bone marrow, and peritoneal membrane, respectively. Both pro-B and pre-B cells can express key genes during B cell development. Clustering results for single-cell sequencing also showed that pro-B and racke pre-B cells regenerated in the early post-transplant stage (Day 7.5) were similar to the corresponding taxa of early B cell development in wild-type mice. In addition, the induced mature B cells have a BCR diversity similar to that of wild-type B cells, and more importantly, the induced B cells have not found clonal proliferation, indicating a very low risk of tumorigenesis. After 4-6 weeks of transplantation, recipient mice can secrete several types of antibodies. After T cell-dependent antigen NP-CGG immunization treatment, recipient mice (immunodeficient mice without endogenous B cells) also perform well in the primary and re-immune responses, manifesting as positive antibody secretion and peak antigen-specific cells versus memory B cells.

The research has been supported by the Chinese Academy of Sciences, the Ministry of Science and Technology, the National Natural Science Foundation of China, Guangdong Province and Guangzhou Municipality.

Guangzhou Institute of Biology realizes the targeted differentiation of pluripotent stem cells to regenerate the B immune lineage

Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences