Cellular Barcoding Links B-1a B Cell Potential to a Fetal Hematopoietic Stem Cell State at the Single-Cell Level

Abstract

Hematopoietic stem cells (HSCs) undergo a functional switch in neonatal mice hallmarked by a decrease in self-renewing divisions and entry into quiescence. Here, we investigated whether the developmental attenuation of B-1a cell output is a consequence of a shift in stem cell state during ontogeny. Using cellular barcoding for in vivo single-cell fate analyses, we found that fetal liver definitive HSCs gave rise to both B-1a and B-2 cells. Whereas B-1a potential diminished in all HSCs with time, B-2 output was maintained. B-1a and B-2 plasticity could be reinitiated in a subset of adult HSCs by ectopic expression of the RNA binding protein LIN28B, a key regulator of fetal hematopoiesis, and this coincided with the clonal reversal to fetal-like elevated self-renewal and repopulation potential. These results anchor the attenuation of B-1a cell output to fetal HSC behavior and demonstrate that the developmental decline in regenerative potential represents a reversible HSC state.

Fetal Lymphoid Progenitors Become Restricted to B-1 Fates Coincident with IL-7Rα Expression

“…Recent studies report neonatal bone marrow CLPs to be more efficient in making B-1 cells than ABM-CLPs but both can make a significant number of B-2 cells [31,32]. In sharp contrast, our data show that FL-CLPs makes few B-2 cells (Fig 1).…”

“…In addition to reports by Barber et al [31] using transplantation setting, a single cellular barcoding technique showed B-1/B-2 bi-potential of FL LT-HSCs [32]. The genetic transition in HSCs during ontogeny resulted in the diminished potential to generate B-1a cells in single cell levels [31].…”

“…The attenuation of B-1 cell development was accompanied by two models, a model based on an apparent wave of the HSC-independent progenitor which has B-1a committed potential [30] and another model based on selective loss of generating B-1a lineages in bona fide HSCs [31,32]. In the latter model, loss of B-1a potential gradually proceeds because many reports have shown the existence of B-1a long-lasting potential in the HSCs in neonatal and adult marrow [31,33,34].…”

Stem Cell Therapeutics of Acute Liver Diseases, Transplantation, and Regeneration

“…This dedifferentiation occurs due to shut down of hepatic genes related to ncRNAs, in particular miRNAs. Moreover, new cellular models can aid the development of more efficient differentiation protocols for stem cellderived hepatocytes which can be used for liver regeneration [88]. Functional hepatocytes derived from human stem cells are used for transplantation purposes to get rid of acute liver injury in experimental animal models.…”

“…These HybHP undergo extensive proliferation, and give rise mature hepatocytes and bile duct cells, and eventually replenish liver mass [94] (Table 2) ( Figure 5). However, in two-dimensional cultures, primary human hepatocytes (PHHs) rapidly dedifferentiate, resulting in loss of hepatic functions that significantly limits their usefulness in vitro model, liver diseases, as well as drug metabolism and toxicity [88] (Figure. 6).…”