Fetal Hematopoietic Stem Cell Transplantation Fails to Fully Regenerate the B-Lymphocyte Compartment

Abstract

SummaryB cells are key components of cellular and humoral immunity and, like all lymphocytes, are thought to originate and renew from hematopoietic stem cells (HSCs). However, our recent single-HSC transfer studies demonstrate that adult bone marrow HSCs do not regenerate B-1a, a subset of tissue B cells required for protection against pneumonia, influenza, and other infections. Since B-1a are regenerated by transfers of fetal liver, the question arises as to whether B-1a derive from fetal, but not adult, HSCs. Here we show that, similar to adult HSCs, fetal HSCs selectively fail to regenerate B-1a. We also show that, in humanized mice, human fetal liver regenerates tissue B cells that are phenotypically similar to murine B-1a, raising the question of whether human HSC transplantation, the mainstay of such models, is sufficient to regenerate human B-1a. Thus, our studies overtly challenge the current paradigm that HSCs give rise to all components of the immune system.

A Transient Developmental Hematopoietic Stem Cell Gives Rise to Innate-like B and T Cells

“…Evidence for this mechanism in humans was recently supported by studies of human T-cell development (Mold et al, 2010). Our discovery of a fetal HSC characterized by lower CD150 expression with distinct innate-like lymphocyte potential is also consistent with a recent report demonstrating that B1 B-cell regenerative capacity mainly reside outside the conventional fetal HSC compartment (Ghosn et al, 2016). The coincidence in existence of the GFP+ HSCs with the perinatal burst in lymphoid development suggests that these HSCs play important roles in specifying innate-like B- and T-cells, while also contributing to robust establishment of adaptive immunity.…”

“…Furthermore, despite lower overall reconstitution levels and limited long-term reconstitution upon in utero transplantation (IUT) (Figure 7H and Table S4), GFP+ KLS cells still retained a greater capability to seed the peritoneal IgM+ B-cell compartment and particularly B1a cells as compared to Tom+ KLS cells upon IUT (Figure 7I). Although a recent report suggested that fetal HSCs are not a major source of B1a cells (Ghosn et al, 2016), we did not observe appreciable regeneration of innate-like B-cells in the absence of LTMR and BM reconstitution (Figure S5). Secondary recipients that did not demonstrate LTMR showed limited ability to reconstitute innate-like lymphocytes in vivo (Figure S5D).…”

A Common Origin for B-1a and B-2 Lymphocytes in Clonal Pre- Hematopoietic Stem Cells

“…Recent reports have strengthened the concept that adult HSCs do not contribute significantly to the innate B-1a cell compartment, but suggest heterogeneity in the fetal HSC compartment with regard to B-1a cell potential (Beaudin et al., 2016, Ghosn et al., 2012, Ghosn et al., 2016, Kristiansen et al., 2016, Sawai et al., 2016). Previous studies by members of our group identified an embryonic HSC-independent B cell progenitor with B-1 but not B-2 cell potential (Kobayashi et al., 2014, Yoshimoto, 2015, Yoshimoto et al., 2011).…”

Age-Related Decline in Natural IgM Function: Diversification and Selection of the B-1a Cell Pool with Age

“…Recently, it was demonstrated B-1a cells develop prior to emergence of hematopoietic stem cells in the yolk sac (YS) and para-aortic splanchnopleura (PSp) endothelium (47, 48). These embryonic and fetal derived B-1 cells are maintained in the adult by self-renewal.…”