Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors

Regeneration of functional B lymphopoiesis from pluripotent stem cells(PSCs)is challenging,and reliable methods have not been developed.Here,we unveiled the guiding role of three essential factors,Lhx2,Hoxa9,and Runx1,the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source.In the presence of Lhx2,Hoxa9,and Runx1 expression,PSC-derived induced hematopoietic progenitors(iHPCs)immediately gave rise to pro/pre-B cells in recipient bone marrow,which were able to further differentiate into entire B cell lineages,including innate B-1a,B-1b,and marginal zone B cells,as well as adaptive follicular B cells.In particular,the regenerative B cells produced adaptive humoral immune responses,sustained antigen-specific antibody production,and formed immune memory in response to antigen challenges.The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells,which eventually formed T cell-dependent humoral responses.This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach,which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.

Senescent bone marrow microenvironment promotes Nras-mutant leukemia

Dear Editor,In recent years,there is growing interest regarding the roles of senescent bone marrow(BM)microenvironment in the initiation of leukemia.Aged mice transplanted with AML1-ETO(AML1-ETO fusion protein)-positive hematopoietic stem cells(HSCs)present with a significant increase in the frequency of AMLETO-positive early progenitor cells in BM as well as an in crease of immature myeloid cells compared to young recipients(Vas et aL,2012).BM mesenchymal stem cells(MSCs)from myelodysplastic syndromes(MDS)animal models and MDS patients exhibit impaired proliferation and differentiation potentials,abnormal cytoki ne secretion,and dysregulated gene expression profile(Lopez-Villar et al.,2009;Geyh et al.,2013;Mattiucci et al.,2018).However,the causal relationship between senes・cent BM microenvironment and leukemia development is unclear.Whether senes・cent BM microenvironment initiates or accelerates leukemia development remains unknown.