The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

Abstract

Myeloid angiogenic cells (MACs) promote revascularization through the paracrine release of angiogenic factors and have been harnessed as therapeutic cells for many ischemic diseases. However, their proangiogenic properties have been suggested to be diminished in diabetes. This study investigates how the diabetic milieu affects the immunophenotype and function of MACs. Both MACs isolated from diabetic conditions and healthy cells exposed to a diabetic environment were used to determine the potential of MACs as a cell therapy for diabetic‐related ischemia. MACs were isolated from human peripheral blood and characterized alongside proinflammatory macrophages M (LPS + IFNγ) and proangiogenic macrophages M (IL4). Functional changes in MACs in response to high‐d‐glucose were assessed using an in vitro 3D‐tubulogenesis assay. Phenotypic changes were determined by gene and protein expression analysis. Additionally, MACs from type 1 diabetic (T1D) patients and corresponding controls were isolated and characterized. Our evidence demonstrates MACs identity as a distinct macrophage subtype that shares M2 proangiogenic characteristics, but can be distinguished by CD163hi expression. High‐d‐glucose treatment significantly reduced MACs proangiogenic capacity, which was associated with a significant increase in IL1β mRNA and protein expression. Inhibition of IL1β abrogated the antiangiogenic effect induced by high‐d‐glucose. IL1β was also significantly upregulated in MACs isolated from T1D patients with microvascular complications compared to T1D patients without microvascular complications or nondiabetic volunteers. This study demonstrates that Type 1 diabetes and diabetic‐like conditions impair the proangiogenic and regenerative capacity of MACs, and this response is mediated by IL‐1β. Stem Cells 2018;36:834–843

Dysfunction and Therapeutic Potential of Endothelial Progenitor Cells in Diabetes Mellitus

“…This incorporation defect is partly attributed to the reduced production of NO in EPCs exposed to high glucose [ 65 ]. In a recently published study, Chambers et al cultured MACs derived from healthy individuals in medium containing high or normal glucose, collected the condition medium and added it to human endothelial colony forming cells (ECFCs) grown in Matrigel, and observed a significant reduction in ECFC tubule formation in the cells receiving the high glucose conditioned medium [ 69 ]. Similar results were obtained when ECFCs were co-cultured with MACs that were previously exposed to high glucose [ 69 ].…”

“…These findings align well with the data presented by Loomans et al [ 59 ]. Gene expression analyses using RT-qPCR identified some important genes dysregulated by high glucose, namely the upregulation of proinflammatory transcripts IL1β, IL6 and IL1α, and downregulation of proangiogenic and anti-inflammatory markers CD163 and CD204 [ 69 ]. The use of a neutralizing antibody against IL1β corrected high glucose induced dysfunction in MACs.…”

SENP1/HIF‐1α axis works in angiogenesis of human dental pulp stem cells

“…Recently, researchers of angiogenesis mostly focused on tumors . Currently, angiogenesis induction and tubulogenesis assay are the main technologies to detect angiogenesis in vitro . The common markers used in the vascular endothelial cell are vWF, VEGFR2, VE‐cad, CD31, and so forth .…”

Vascular Regeneration for Ischemic Retinopathies: Hope from Cell Therapies

“…78 Furthermore, MACS cultured under in vitro diabetes-like conditions and isolated from type 1 diabetic patients have been shown to increase the gene expression of IL-1β, IL-6, IL-1α, ICAM-1 and IL-8, which is akin to M1 macrophages. 79 Therefore, the phenotypic plasticity and altered functionality of MACs under diabetes pathology needs to be fully investigated prior to successful implementation of an autologous MACs therapy for retinal ischemic diseases.…”