Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy

Stem Cells. 2016 Feb;34(2):405-17. doi: 10.1002/stem.2235. Epub 2015 Nov 17.

Abstract

Ataxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR.

Keywords: Ataxia telangiectasia mutated; Diabetic retinopathy; Hematopoietic stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / biosynthesis*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Female
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Up-Regulation*

Substances

  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse