B cells are essential for a functional and complete humoral immune system. With certain disease conditions, the B lymphopoiesis and serum immunoglobulin levels are severely impaired, resulting in infections in patients. Regeneration of autologous and normal B cells from pluripotent stem cells (PSCs) is ideally viableto solve the abnormal B cell-related problems. However, it is difficult to obtain mature B cells in vitro due to lack of methods of simulating the spatiotemporal microenvironments of B cell development in natural spleen.
In a study published in Cellular & Molecular Immunology, a team of researchers led by Dr. Wang Jinyong from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, identified that synergistic expression of exogenous Lhx2, Hoxa9, and Runx1 dominantly confers a B cell lineage fate from PSCs and leads to complete B lymphopoiesis and serum antibody generation in B-cell deficient animals.
The study established a two-step approach of in vitro upstream hematopoietic progenitor (iHPC) generation plus in vivo B cell development via iHPC transplantation to achieve B cell regeneration. The regeneration of B cells is robust and reproduces pro-B progenitors, pre-B progenitors, immature B cells, and all subsets of mature B-1a, B-1b, FO B, and MZ B cells. Single-cell RNA-seq showed that regenerative pro-B and pre-B cells resembled their natural cell counterparts and expressed key regulators of early B cell development. Induced mature B cells exhibited abundant B cell repertoires with the ability of producing serum IgM, IgG1, IgG2b, IgG2c, IgG3, and IgA antibodies. In responding to T cell-dependent antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory.
This is the first report of achieving engraftable, functional, and complete regenerative B lymphopoiesis from pluripotent stem cells, which provides insights into clinical translation of B cell-based therapy using unlimited PSC resource.
B cell regeneration from pluripotent stem cells