Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

Forsberg, Camilla

doi:10.1101/2020.01.08.899427

Cited by 5 publications

(4 citation statements)

References 100 publications

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“…All experiments were performed using 8-to 12-week-old C57BL/6 wild-type mice in accordance with UCSC IACUC guidelines. Hematopoietic cells were isolated from BM by crushing murine femurs, tibias, hips, and sternums as previously described (Rajendiran et al, 2020). Stem and progenitor cell fractions were enriched using CD117-coupled magnetic beads (Miltenyi).…”

Section: Methodsmentioning

confidence: 99%

Chromatin Accessibility Maps Provide Evidence of Multilineage Gene Priming in Hematopoietic Stem Cells

Martin¹,

Krietsch²,

Reggiardo³

et al. 2020

Preprint

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Hematopoietic stem cells (HSCs) have the capacity to differentiate into vastly different types of mature blood cells. The epigenetic mechanisms regulating the multilineage ability, or multipotency of HSCs are not well understood. To test the hypothesis that cis regulatory elements that control fate decisions for all lineages are primed in HSCs, we used ATAC-seq to compare chromatin accessibility of HSCs with five unipotent cell types. We observed the highest similarity in accessibility profiles between Megakaryocyte Progenitors and HSCs, whereas B cells had the greatest number of regions with de novo gain in accessibility during differentiation. Despite these differences, we identified cis regulatory elements from all lineages that displayed epigenetic priming in HSCs. These findings provide new insights into the regulation of stem cell multipotency, as well as a resource to identify functional drivers of lineage fate.HIGHLIGHTSHSCs have higher global chromatin accessibility than any unilineage progenyMegakaryocyte Progenitors are the most closely related unipotent cell type to HSCsB cell commitment involves de novo chromatin accessibilityEvidence of cis element priming of lineage-specific genes in HSCs

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Section: Methodsmentioning

confidence: 99%

Chromatin Accessibility Maps Provide Evidence of Multilineage Gene Priming in Hematopoietic Stem Cells

Martin¹,

Krietsch²,

Reggiardo³

et al. 2020

Preprint

Self Cite

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“…Second, we removed the host cell variable by quantifying the absolute numbers of donor-derived mature cells in the PB of recipient mice (Boyer et al, 2019;Cool et al, 2020;Rajendiran et al, 2020aRajendiran et al, , 2020b to more quantitatively assess the differences in regenerative activity between young and old HSCs. Old HSCs generated fewer erythroid, GM, B, T, and Plt cells compared with young HSCs (Figure 2C); this observation is consistent with host cell production presented as donor-derived chimerism (Figure 2B).…”

Section: Old Hscs Exhibit Impaired Reconstitution Potential Compared With Young Hscsmentioning

confidence: 99%

Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells

et al. 2021

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Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. Although young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared with young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging.

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“…We therefore investigated mice overexpressing the ligand CXCL12 70 . in vivo short term application of CXCL12 has recently been described to lead to increased CXCR4 signaling 71 . On the other hand, continuous treatment with the ligand CXCL12 reduced the CXCR4 level in cortical interneurons, 45 and CXCL12 accumulation triggers CXCR4 endocytosis and degradation, with defects in CXCR4‐mediated functions 44 .…”

Section: Discussionmentioning

confidence: 99%

Chemokine signaling is required for homeostatic and injury-induced neurogenesis in the olfactory epithelium

et al. 2021

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The olfactory epithelium (OE) possesses unique lifelong neuroregenerative capacities and undergoes constitutive neurogenesis throughout mammalian lifespan. Two populations of stem cells, frequently dividing globose basal cells (GBCs) and quiescent horizontal basal cells (HBCs), readily replace olfactory neurons throughout lifetime. Although lineage commitment and neuronal differentiation of stem cells has already been described in terms of transcription factor expression, little is known about external factors balancing between differentiation and self-renewal. We show here that expression of the CXC-motif chemokine receptor 4 (CXCR4) distinguishes both types of stem cells. Extensive colocalization analysis revealed exclusive expression of CXCR4 in proliferating GBCs and their neuronal progenies. Moreover, only neuronal lineage cells were derived from CXCR4-CreER-tdTomato reporter mice in the OE. Furthermore, Cre-tdTomato mice specific for HBCs (Nestin+ and Cytokeratin14+) did not reduce CXCR4 expression when bred to mice bearing floxed CXCR4 alleles, and did not show labeling of the neuronal cells. CXCR4 and its ligand CXCL12 were markedly upregulated upon induction of GBC proliferation during injury-induced regeneration. in vivo overexpression of CXCL12 did downregulate CXCR4 levels, which results in reduced GBC maintenance and neuronal differentiation. We proved that these effects were caused by CXCR4 downregulation rather than over-activation by showing that the phenotypes of CXCL12-overexpressing mice were highly similar to the phenotypes of CXCR4 knockout mice. Our results demonstrate functional CXCR4 signaling in GBCs regulates cell cycle exit and neural differentiation. We propose that CXCR4/CXCL12 signaling is an essential regulator of olfactory neurogenesis and provide new insights into the dynamics of neurogenesis in the OE.

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Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

Cited by 5 publications

References 100 publications

Chromatin Accessibility Maps Provide Evidence of Multilineage Gene Priming in Hematopoietic Stem Cells

Chromatin Accessibility Maps Provide Evidence of Multilineage Gene Priming in Hematopoietic Stem Cells

Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells

Chemokine signaling is required for homeostatic and injury-induced neurogenesis in the olfactory epithelium

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