Manchev, V. T. | Search bioRxiv

bioRxiv2026

Modeling human B cell development with pluripotent stem cells

The ability to generate functional B cells from human pluripotent stem cells (hPSCs) would open new opportunities to develop novel B cell-based therapies to treat a range of human diseases and disorders. Towards this goal, we established a protocol that promotes the efficient development of B lineage cells from definitive hematopoietic progenitors generated from different hPSC lines. Flow cytometric and multi-omic scRNA-seq analyses revealed that B cell development from hPSCs transitions through the well-established pro-B, pre-B and naive B cell stages, accurately recapitulating B lymphopoiesis in the human adult bone marrow. Importantly, the naive B cells generated with this approach could be induced to mature into plasma cells that secrete antibodies and undergo class switching. Analyses of signaling pathways that regulate B lymphopoiesis in these cultures uncovered a potent inhibitory effect of IL-7 on functional IgH rearrangement, resulting in the development of abnormal cells that failed to undergo pre-B cell maturation. Finally, analysis of the different hPSC-derived hematopoietic programs revealed that both definitive and yolk sac progenitors display B cell potential, indicating that there are distinct developmental sources of human B lineage cells. Taken together, these findings demonstrate the efficient generation of B cells from hPSCs and, in doing so, provide a system for further investigating the earliest stages of human B lymphopoiesis and a source of appropriately staged plasma cells for future therapeutic applications.

developmental biology↗

bioRxiv2022

ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis

Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes Thrombocytopenia 2 (THC2), an inherited platelet disorder associated with leukemia predisposition. Some of those patients present also erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patient cells and patient-derived iPSCs) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly impacts the proliferation/differentiation balance for these three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization, which leads to increased signaling and cytokine hypersensitivity. Altogether these findings show that ANKRD26 overexpression or the absence of its silencing during differentiation are responsible for myeloid blood cell abnormalities in THC2 patients.

cell biology↗