Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells

Abstract

In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis.

Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice

“…Next, we assessed whether CSF1R is expressed in the fetal multipotent stem and progenitor cells preceding B-cell lineage commitment. In agreement with previous studies, 15,27 23% and 9% of lymphoid-primed multipotent progenitors (LMPPs; Lin -KIT high SCA-1 high FLT3 high ) expressed CSF1R in E13.5 and E14.5 FL, respectively, whereas 6% of LMPPs in adult BM were CSF1R-positive ( Figure 1D-E). In contrast, there was almost no detectable CSF1R expression on HSCs (Lin…”

“…12 In adult hematopoiesis, CSF1R has been shown to be highly and selectively expressed on myeloid and dendritic cells, but to be undetectable on lymphocytes, including progenitors and mature cells of the B-cell lineage. 13,14 Recently early lympho-myeloid progenitor cells in the mouse embryo, possessing combined B, T, and myeloid-lineage potential, but not megakaryocyte-erythroid-lineage potential, were found to coexpress CSF1R and IL7 receptor (IL-7R), 15,16 suggesting that CSF1R might not exclusively play a role in myelopoiesis, and a potential role in early embryonic lympho-myeloid development. Thus, although a number of studies have provided support for a strong link between fetal B and myeloid lineage development and the potential existence of a fetal B myeloid-restricted progenitor, such a progenitor has yet to be prospectively identified and characterized.…”

Trap1a is an X-linked and cell-intrinsic regulator of thymocyte development

“…We carried out in silico analyses for Trap1a expression. As shown in Figure 5c, RNAseq data 15 showed that Trap1a was not expressed in thymocytes, whereas databases generated by others 18,19 revealed low levels of expression in BM LSK stem/progenitor cells and CLP cells (Figure 5d). Because thymocyte progenitors were identified as part of the LSK population, 21 we used PCR to validate Trap1a expression in LSK cells.…”

“…16 Then, the gene expression level was measured by RPKM and calculated by DEGseq. 17 The expression values of hematopoietic stem cells, LSK and common lymphoid progenitors (CLP) were extracted from the expression result file through GEO Series accession numbers GSE50896 18 and GSE50739. 19 …”

Checkpoints that control B cell development

“…These B cells persist after birth, are mostly resting, and are radio resistant. The precursors of BIa B cells disappear early in life (10). Precursors of later B cell development, generated from pHSCs in bone marrow and used in the clinical setting of bone marrow transplantation to restore hematopoiesis and lymphopoiesis, can no longer develop these long-lived BIa cells.…”