Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy

Ashay D. Bhatwadekar, Yaqian Duan, Harshini Chakravarthy, Maria Korah, Sergio Caballero, Julia V. Busik, Maria B. Grant

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)405-417
Number of pages13
JournalSTEM CELLS
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • Ataxia telangiectasia mutated
  • Diabetic retinopathy
  • Hematopoietic stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Bhatwadekar, A. D., Duan, Y., Chakravarthy, H., Korah, M., Caballero, S., Busik, J. V., & Grant, M. B. (2016). Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy. STEM CELLS, 34(2), 405-417. https://doi.org/10.1002/stem.2235