Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy.
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.
Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA.|Department of Pharmacology and Therapeutics, University of Florida, Florida, USA.
Ashay D
AD
Bhatwadekar
Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA.
Yaqian
Y
Duan
Department of Physiology, Michigan State University, East Lansing, Michigan.
Harshini
H
Chakravarthy
Department of Pharmacology and Therapeutics, University of Florida, Florida, USA.
Maria
M
Korah
Department of Pharmacology and Therapeutics, University of Florida, Florida, USA.
Sergio
S
Caballero
Department of Physiology, Michigan State University, East Lansing, Michigan.
Julia V
JV
Busik
Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA.|Department of Pharmacology and Therapeutics, University of Florida, Florida, USA.
Maria B
MB
Grant
D000328:Adult; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D015854:Up-Regulation
C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
Ataxia telangiectasia mutated; Diabetic retinopathy; Hematopoietic stem cells