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  • Here we resolve this issue by showing that

    2018-11-08

    Here, we resolve this issue by showing that, similar to adult BM, fetal liver LT-HSCs effectively regenerate FO, MZ, transitional, B-1b, and peripheral blood B cells but still fail to regenerate B-1a. These findings provide further evidence that B-1a emerge as a separate B-cell lineage that develops independently of LT-HSCs. Consistent with these findings, we show that fetal liver LT-HSCs also fail to reconstitute a key component of the B-1a repertoire (i.e., VH11), which produce anti-phospholipid ion channel known to promote housekeeping activities and prevent autoimmunity (Behar and Scharff, 1988; Elkon and Silverman, 2012; Nguyen et al., 2015). Together, these studies challenge the broadly accepted paradigm that LT-HSCs can give rise to all components of the immune system. We discuss these findings in light of recent studies showing that this HSC-independent developmental strategy may also apply in other hematopoietic lineages (Ginhoux et al., 2010; Schulz et al., 2012; Yoshimoto et al., 2012). Furthermore, from a medical standpoint, we call into question current human regenerative therapies in which HSC transplantation is used to restore immunity in immune-compromised individuals, and consider the probable shortcomings of an immune system that lacks the B-1a cell subset.
    Results
    Discussion Here, we define a lineage of tissue B cells that originates independently of the fetal liver LT-HSC. In essence we show that, in a transplantation setting, fetal liver LT-HSCs selectively fail to regenerate B-1a cells in otherwise fully reconstituted hosts. These findings call into question the current view that HSCs regenerate all components of the immune system, a view of particular importance to modern medicine, since HSC transplantation is broadly used to restore immune function in patients in whom the immune system has been compromised (Czechowicz and Weissman, 2011; Liang and Zuniga-Pflucker, 2015; Pasquini and Zhu, 2014). Our data demonstrate that at least two B-cell lineages overlap in development during ontogeny and are independently renewed throughout life. The B-2 lineage, which mainly gives rise to FO, MZ, transitional, and B-1b B cells, originates and is continually renewed by HSCs located in both fetal liver and adult BM. In contrast, the B-1a lineage, which gives rise to B cells located mainly in pleural and peritoneal cavities, omentum, and spleen, originates in the fetus independently of liver HSCs and persists independently via self-renewal throughout life. These developmental distinctions between the lineages to which B-1a and B-2 belong, i.e., HSC-independent versus HSC-dependent, likely reflect a deeper development schism that transcends the development of all mammalian hematopoietic lineages. In both mice and humans, the first source of hematopoietic cells found during ontogeny is located extra-embryonically in the yolk sac, in an anatomic region known as the blood islands (Lux et al., 2008; Moore and Metcalf, 1970; Ueno and Weissman, 2006). Fetal nucleated erythrocytes are the first hematopoietic lineage to emerge within the blood islands at ∼E7 (Palis et al., 1999), prior to and independent of the development of HSCs. Similarly, tissue macrophages, such as brain microglia, epidermal Langerhans cells, and some subsets of liver Kupffer cells, originate in the yolk sac at ∼E8, prior to the development of HSCs (Ginhoux et al., 2010; Schulz et al., 2012). Animals deficient in HSCs normally generate these tissue macrophages, despite their inability to reconstitute HSC-dependent macrophages, such as those derived from LY6-Chi monocytes (Hashimoto et al., 2013; Schulz et al., 2012). This initial wave of HSC-independent erythrocyte-myeloid development in the yolk sac (Lux et al., 2008; Palis et al., 1999) is immediately followed by an initial wave of lymphopoiesis (Boiers et al., 2013; Yoshimoto et al., 2011, 2012). Recent studies, using Rag1-GFP reporter mice, show that the earliest lymphomyeloid-primed progenitors (Lin–C-KIT+RAG1GFP+IL7Ra+) can be detected in the yolk sac at ∼E9, prior to HSC development (Boiers et al., 2013). Consistent with this finding, E9 yolk sac endothelium can differentiate into B-1-restricted progenitors in vitro, and reconstitute both B-1 and MZ B, but not B-2, in adoptive transfer recipients (Yoshimoto et al., 2011). Similarly, fetal T-cell progenitors have been reported to originate autonomously in E9 yolk sac prior to the development of HSCs (Yoshimoto et al., 2012). Taken together, these studies suggest that HSC-independent hematopoiesis occurs for the lymphoid, myeloid, and erythroid lineages. We therefore propose that the development of HSC-independent hematopoietic cells in early embryos reflects an overall developmental strategy of the immune system, which initiates the first waves of “primitive” hematopoietic cells carrying evolutionarily conserved functions that are distinct from the HSC-derived cell and functions of the adaptive immune system operating in adults.