Diabetes affects recovery from ischemic insult by blunting the neovascular response. Ischemic neovascularization occurs via two fundamentally different pathways: the sprouting of new blood vessels from existing vessels (angiogenesis), and the recruitment, proliferation, and assembly of bone marrow-derived progenitor cells into new vessels (vasculogenesis). Our work over the last four years has shown that diabetes impairs new blood vessel formation in response to hypoxia by causing abnormal ischemia-induced signaling as well as impaired progenitor cell proliferation, function, and trafficking (i.e. impaired vasculogenesis). We have shown that these derangements in progenitor cells are caused in part by reactive oxygen species (ROS), which reduce the number and function of bone marrow-derived mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs). Normalizing blood glucose does not reverse these effects, which may contribute to the phenomenon known as hyperglycemic memory. It is our fundamental hypothesis that diabetes- induced derangements in progenitor cell biology underlie the observed impairments in ischemia- induced vasculogenesis. In this proposal, we will determine how bone marrow-derived mesenchymal stem cells contribute to the development of new blood vessels in the setting of hypoxia (SA1), examine the how hyperglycemia alters these progenitor cell populations, including MSCs and HSCs (SA2), and clarify how hyperglycemia-induced ROS alters pathways affecting cell cycle progression and decreased stem cell capacity in MSCs, EPCs and HSCs (SA3). Finally, to determine the clinical relevance of our findings, we will examine human circulating EPCs and bone marrow-derived MSCs and HSCs from non-diabetic and diabetic patients (SA4).

Public Health Relevance

Diabetes is a major public health concern in the United States, accounting for 180 billion dollars in annual health costs. Diabetes-induced impairments in new blood vessel growth greatly increase the severity of the sequelae caused by various ischemic processes, including coronary artery disease, cerebrovascular disease, peripheral vascular disease and impaired wound healing. Recovery from ischemic injury requires new blood vessel growth, termed neovascularization, and requires functional participation by stem and progenitor cells. There is growing evidence that diabetes directly impairs progenitor cell function and impairs neovascularization. This proposal takes an innovative approach to elucidate this dysfunction and find new ways to approach diagnosis and treatment of diabetic vascular complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074095-10
Application #
8452121
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2005-09-30
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$450,529
Indirect Cost
$122,886
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Duscher, Dominik; Atashroo, David; Maan, Zeshaan N et al. (2016) Ultrasound-Assisted Liposuction Does Not Compromise the Regenerative Potential of Adipose-Derived Stem Cells. Stem Cells Transl Med 5:248-57
Kosaraju, Revanth; Rennert, Robert C; Maan, Zeshaan N et al. (2016) Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds. Tissue Eng Part A 22:295-305
Shah, Manasi S; Brownlee, Michael (2016) Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. Circ Res 118:1808-29
Whittam, Alexander J; Maan, Zeshaan N; Duscher, Dominik et al. (2016) Challenges and Opportunities in Drug Delivery for Wound Healing. Adv Wound Care (New Rochelle) 5:79-88
Duscher, Dominik; Luan, Anna; Rennert, Robert C et al. (2016) Suction assisted liposuction does not impair the regenerative potential of adipose derived stem cells. J Transl Med 14:126
Duscher, Dominik; Maan, Zeshaan N; Whittam, Alexander J et al. (2015) Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing. Plast Reconstr Surg 136:1004-13
Rodrigues, Melanie; Wong, Victor W; Rennert, Robert C et al. (2015) Progenitor cell dysfunctions underlie some diabetic complications. Am J Pathol 185:2607-18
Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W et al. (2015) Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci U S A 112:94-9
Chang, Edwin; Paterno, Josemaria; Duscher, Dominik et al. (2015) Exercise induces stromal cell-derived factor-1α-mediated release of endothelial progenitor cells with increased vasculogenic function. Plast Reconstr Surg 135:340e-50e
Wan, Derrick C; Gurtner, Geoffrey C; Longaker, Michael T (2015) Reply: Studies in fat grafting: part I. Effects of injection technique on in vitro fat viability and in vivo volume retention; and studies in fat grafting: part II. Effects of injection mechanics on material properties of fat. Plast Reconstr Surg 135:448e-9e

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