Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

Abstract

Recruitment of innate immune cells from the bone marrow (BM) to an injury site is required for effective repair. In diabetes, this process is altered, leading to excessive recruitment and retention of dysfunctional myeloid cells that fail to promote angiogenesis, prolong inflammation, and block healing. The aberrant myeloid phenotype is partially mediated by stable intrinsic changes to developing cells in the BM that are induced by the diabetic (db) environment, but the exact mechanisms remain largely unknown. Here, we show that the db-derived Gr-1+CD11b+ immature myeloid population has widespread misexpression of chromatin-remodeling enzymes and myeloid differentiation factors. Crucially, diabetes represses transcription of the key myeloid transcription factor CEBPA via diminished H3 Lys 27 promoter acetylation, leading to a failure in monocyte and granulocyte maturation. Restoring Cebpa expression by granulocyte colony-stimulating factor reverses the db phenotype and rescues myeloid maturation. Importantly, our data demonstrate a possible link between myeloid cell maturation and chronic inflammation.

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

“…Microarray hybridization onto HumanHT-12 v4 BeadChip (Illumina, San Diego, CA, USA) containing 47,231 gene probes was performed in the Yale Center for Genome Analysis (Orange, CT, USA). Raw data was analyzed with R (R Foundation for Statistical Computing, Vienna, Austria)/Bioconductor (Seattle, WA, USA) and MicroarrayRUS software (34). Data were log transformed and quantile normalized.…”

Cx3CR1 Expression Identifies Distinct Macrophage Populations That Contribute Differentially to Inflammation and Repair

“…Current therapies for chronic diabetic wounds primarily target the symptoms of the diabetic changes in wound pathology, with poor healing outcomes in many patients (2). To better understand the etiology behind diabetic wounds there has been much focus upon the role of inflammatory cell populations within the wound environment and how they may be altered in diabetes (3)(4)(5)(6)(7).…”

Роль Нейтрофильных Лейкоцитов В патогенезе Сахарного Диабета 1-Го Типа У человека (Аналитический Обзор С включением Собственных Данных)

“…В то же время в исследованиях, проведенных на мышах, было показано [43], что при СД происходит блокада созревания незрелых миелоидных клеток Gr-1+CD 11b+, включающих нейтрофилы в костном мозге (КМ), что обусловлено репрессией ключевого миелоидного транскрипционного фактора СЕВРА. Причем введение Г-СКФ приводит к восстановлению нормального нейтрофилопоэза у диабетических мышей.…”