Author response: Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging

Säwén, Petter; Eldeeb, Mohamed; Erlandsson, Eva; Kristiansen, Trine A.; Laterza, Cecilia; Kokaia, Zaal; Karlsson, Göran; Yuan, Joan; Soneji, Shamit; Mandal, Pankaj Kumar; Rossi, Derrick J.; Bryder, David

doi:10.7554/elife.41258.018

Cited by 2 publications

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“…B-1a B cells mainly derive from the fetal liver (FL) and neonatal tissues, but can develop, albeit less efficiently, from adult bone marrow (BM) where B-2 differentiation predominates (1,5,19,(22)(23)(24). A temporal and anatomic switch in primary B cell development is mediated by the Let7-Lin28b-Arid3a axis that differentially regulates B-1 development during fetal vs. adult life (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection

et al. 2020

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B-1a cells produce "natural" antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the fundamental selection mechanisms that shape their polyreactive repertoires are poorly understood. Here, we identified a B cell progenitor subset defined by Fc receptor-like 6 (FCRL6) expression, harboring innate-like defense, migration, and differentiation properties conducive for natural Ab generation. Compared to FCRL6 − pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6 + progenitors, yielded V H repertoires with biased distal Ighv segment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Beyond nascent autoreactivity, V H 11 productivity, which predominates phosphatidylcholine-specific B-1a B cell receptors (BCRs), was higher for FCRL6 + cells as was pre-BCR formation, which was required for Myc induction and V H 11, but not V H 12, B-1a development. Thus, FCRL6 revealed unexpected heterogeneity in the developmental origins, regulation, and selection of natural Abs at the pre-BCR checkpoint with implications for autoimmunity and lymphoproliferative disorders.

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Section: Introductionmentioning

confidence: 99%

Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection

et al. 2020

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Hematopoietic stem cells self-renew symmetrically or gradually proceed to differentiation

Barile

Busch

Fanti

et al. 2020

Preprint

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SUMMARYIt is not known whether hematopoietic stem cells (HSCs) undergo symmetric or asymmetric cell divisions in the unperturbed bone marrow. Here, we integrate data from HSC fate mapping and cell-cycle-dependent labeling through mathematical inference and thus gain insight into how HSCs coordinate self-renewal with differentiation. We find that most HSC divisions in adult mice are symmetric self-renewing, replacing HSCs lost by direct differentiation and death, and slowly expanding the HSC population. This expansion maintains constant HSC output to multipotent progenitors (MPPs), despite declining HSC differentiation rate with age. We identify a linear hierarchy of differentiation states between tip HSCs and MPPs, where Tie2-driven HSC fate mapping fully covers the progression of the differentiating cells. A turning point from self-renewal to accelerated cell differentiation occurs between early-stage and late-stage MPPs, just before lineage differentiation becomes manifest in single-cell transcriptomes. This stem cell hierarchy precedes lineage differentiation and may limit mutation accumulation in the hematopoietic system.

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Author response: Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging

Cited by 2 publications

References 0 publications

Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection

Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection

Hematopoietic stem cells self-renew symmetrically or gradually proceed to differentiation

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