Dataset Information

Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus.

ABSTRACT:

Background

Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.

Methods

In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.

Results

In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (Cdh5^Cre Egfr^fl/fl). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5^Cre Egfr^fl/fl mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5^Cre Egfr^fl/fl mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5^Cre Egfr^fl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.

Conclusions

In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.

SUBMITTER: Hoyer FF

PROVIDER: S-EPMC7375017 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background—Diabetes is a prevalent public health problem that affects about one third of the U.S. population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes complications is incompletely understood. We thus investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. Methods and Results—In three types of mouse diabetes, we observed enhanced proliferation of hematopoietic stem and progenitor cells (HSPC) leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (EGFR) signaling in mice with diet-induced diabetes. To explore whether endothelial EGFR plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of EGFR (Cdh5Cre EGFRfl/fl). Unexpectedly, we found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre EGFRfl/fl mice compared to wild type mice with diabetes. Disrupted EGFR signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre EGFRfl/fl mice, significantly delaying wound closure. Atherosclerosis accelerated in Cdh5Cre EGFRfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta. Conclusions—In diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis and promote cardiovascular complications via leukocyte overproduction. Specifically, diabetes reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We also describe a previously unknown counter-regulatory pathway, in which protective endothelial EGFR signaling curbs HSPC proliferation and myeloid cell production via angiopoietin-1.