Molecular Signatures of Tissue-Specific Microvascular Endothelial Cell Heterogeneity in Organ Maintenance and Regeneration

Abstract

SUMMARY Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration.

The Hematopoietic Chemokine CXCL12 Promotes Integration of Human Endothelial Colony Forming Cell–Derived Cells into Immature Vessel Networks

“…Studies by other researchers have shown that CXCR4 is upregulated on endothelial cells by VEGF-A, VEGF-C, or FGF-2, that CXCL12 (SDF-1a) acts synergistically with SCF and IL-3 to promote vascular lumen formation in vitro, and that Flt3-ligand or M-CSF can replace SCF as a costimulatory cytokine in this process [39,43]. In this context, we and others have shown that these synergistic factors are differentially produced by hBM MSCs, hDFs, or human UC or CB ECFC-derived cells in vitro [35,36,[44][45][46][47], so that a loss of supporting stromal cells and hence of their secreted factors would result in reduced tubule formation. Notably, despite the contribution of a number of factors to vessel formation in this assay, blockade of CXCL12 with AMD3100 alone had a significant effect on vascular tubule formation, implying that it is a key molecule in this process.…”

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

“…During development, the endothelium provides paracrine signals to assist the formation of various organs, including liver and pancreas (9,10). Emerging evidence indicates that ECs also regulate postnatal homeostatic and regenerative processes via paracrine production of stem cell-active trophic factors (11). For example, signals from bone marrow microvascular ECs are essential for selfrenewal and repopulation of hematopoietic stem cells (12).…”

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

“…Earlier studies found that the number of HSCs was not decrease in mice with a reduced number of mature osteoblasts [53,91]. And, finally, conditional deletion of CXCL12 [92][93][94][95][96] or SCF [94] in the mature osteoblasts did not affect bone marrow HSCs content.…”

“…The conditional deletion of CXCL12 in the Osx + cells [93], Col2,3-Cre osteoblasts [92,95] or BGLAP-Cre osteoblasts [96] does not lead to any defects in the HSCs. At the same time, deletion of CXCL12 in the osteoblasts (Col2,3-Cre) is accompanied with the decrease of common lymphoid progenitors in the BM [92], while deletion in the Osx + osteogenic cells leads to the decrease of the number of the committed lymphoid precursors of the В-lymphocytes [93].…”