Role of endothelial Dlc1 in embryonic vascular development and adult bone marrow hematopoiesis.
Dlc1 is identified as a key regulator of vascular development and hematopoiesis in bone marrow, but further research is needed to understand its implications in human health.
Where it sits
this study against the rest of the mk-677 (ibutamoren) corpusSummary and findings
This study investigates the role of Dlc1 in endothelial cells and its impact on vascular development and hematopoiesis in bone marrow. The research was conducted in adult mice with inducible EC-specific Dlc1 deletion. The findings indicate significant disruptions in bone marrow vascular architecture and hematopoietic progenitor cells.
Abstract
Bone marrow endothelial cells (ECs) form specialized vascular niches that support hematopoietic stem and progenitor cells (HSPC), yet the molecular regulators of this function remain incompletely defined. Here, we identify the Rho GTPase-activating protein Dlc1 as an essential regulator of developmental vasculogenesis, and adult bone marrow vascular niche integrity. Endothelial-specific deletion of Dlc1 caused embryonic lethality with severe vascular defects. In adult mice, inducible EC-specific Dlc1 deletion disrupted the bone marrow vascular architecture, associated with a significant reduction of multipotent hematopoietic progenitors and myeloid-lineage cells. Single-cell RNA sequencing revealed transcriptional reprogramming of Dlc1-deficient ECs, with the emergence of cell subsets displaying altered transcriptional profiles and disrupted expression of key niche signals, including Kitl, Cxcl12, and Pdgfb. Ligand-receptor interactome analysis demonstrated impaired EC-to-HSPC communication, and the hematopoietic cells exhibited transcriptional features of metabolic stress and reduced biosynthetic activity. These findings position Dlc1 as a central regulator of developmental vasculogenesis, adult vascular architecture in the bone marrow, and EC-derived hematopoietic cell support. This work uncovers a previously unrecognized role for Dlc1 in coupling vessel function to hematopoietic cell output, with implications for understanding bone marrow failure syndromes and targeting endothelial dysfunction in hematologic diseases.