Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow

Abstract

Endothelial cells (ECs) contribute to haematopoietic stem cell (HSC) maintenance in bone marrow, but the differential contributions of EC subtypes remain unknown, owing to the lack of methods to separate with high purity arterial endothelial cells (AECs) from sinusoidal endothelial cells (SECs). Here we show that the combination of podoplanin (PDPN) and Sca-1 expression distinguishes AECs (CD45− Ter119− Sca-1bright PDPN−) from SECs (CD45− Ter119− Sca-1dim PDPN+). PDPN can be substituted for antibodies against the adhesion molecules ICAM1 or E-selectin. Unexpectedly, prospective isolation reveals that AECs secrete nearly all detectable EC-derived stem cell factors (SCF). Genetic deletion of Scf in AECs, but not SECs, significantly reduced functional HSCs. Lineage-tracing analyses suggest that AECs and SECs self-regenerate independently after severe genotoxic insults, indicating the persistence of, and recovery from, radio-resistant pre-specified EC precursors. AEC-derived SCF also promotes HSC recovery after myeloablation. These results thus uncover heterogeneity in the contribution of ECs in stem cell niches.

Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation

“…Arterial and sinusoidal endothelial cells (AECs and SECs) can be distinguished by specific marker expression (Gomariz et al, 2018;X. M. Li et al, 2009;Smith-Berdan et al, 2015), express varying levels of SCF and CXCL12 and regulate different aspects 5 of hematopoiesis (Ding et al, 2012;Xu et al, 2018), from HSC maintenance to maturation of megakaryocytes and late B cell differentiation (Lazzari and Butler, 2018;Stegner et al, 2017).…”

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

“…While the perivascular niche has emerged in recent studies as an important microenvironment for HSCs, many questions remain about how it supports HSCs. 2,8,53,61,71 Technologies to examine multicellular cultures provide the potential to examine how HSCs relate to niche cells around them. Our lab has previously shown the use of biomaterial design principles to effectively regulate cellular crosstalk as a critical feature for in vitro HSC culture.…”

“…1,15,42,53 Further investigation has shown that the perivascular niche provides biomolecular signals that can influence HSC function (i.e., SCF, FGF2, IGFBP2, DLL1) implicating the perivascular secretome in influencing HSC fate decisions. 21,40,71 Many such studies have been performed in vivo, where a complex microenvironment makes it difficult to observe the direct effects of any experimental conditions. 2,21,34,42 Tissue engineering platforms provide the potential to control the complexity of the extracellular environment in order to parse out effects of multiple niche components.…”

Induction of developmental hematopoiesis mediated by transcription factors and the hematopoietic microenvironment

“…ECs are major sources of cytokines, such as C-X-C motif chemokine 12 (CXCL12) and SCF, that control HSC function. [111][112][113][114] ECs also express the angiocrine factor Jagged-1 through which they control homeostatic and regenerative hematopoiesis in a Notch-dependent manner. 115,116 The importance of ECs in HSC regulation is further supported by data demonstrating that ECs boost the formation of hematopoietic multipotent progenitors from pluripotent stem cells, 117 promote the reprogramming of human and mouse ECs to HCs, 20,74 and support the ex vivo expansion of BM-repopulating HSPCs.…”