HSC-independent definitive lymphopoiesis persists into adult life

Abstract

Abstract The stem cell theory that all blood cells are derived from hematopoietic stem cell (HSC) is a central dogma in hematology. However, exceptions are the fetal hematopoiesis in which primitive and definitive type of erythromyeloid cells are already produced from hemogenic endothelial cells (HECs) before the first HSC emergence in the mouse embryo. This early blood cell production prior to HSC emergence is called HSC-independent hematopoiesis and considered to be transient during fetus. Recent lineage-tracing studies revealed that some tissue-resident innate immune cells (e.g. brain microglia, mast cells, and certain types of γδT cells) are also produced independently of HSCs from early extra-embryonic yolk-sac (YS). Definitive T&B-lymphoid potential and multi-potent progenitor (MPP) potential have been detected in the YS and/or embryos in in vitro studies, however, the physiological presence of these cells in the embryo at pre-HSC stage remains unknown. In addition, whether HSCs in the fetal liver are the main source of innate-like B-1a cells has been controversial. Here, using complementary lineage tracing mouse models, we show that HSC-independent MPPs and HSC-independent adoptive T & B-lymphocytes persist into adult life and are gradually replaced by HSC-derived cells. Furthermore, we found that HSCs minimally contribute to the peritoneal B-1a cells, and most B-1a cells are originated directly from ECs in the YS and embryo and HSC-independent for life. Our discovery of extensive HSC-independent MPP and adoptive lymphocytes in adults attests to the complex blood developmental dynamics through embryo to adult that underpin the immune system and challenges the paradigm of HSC theory in hematology. Supported by grant from NIH R01AI121197.