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).
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.
|Bonham, Clark A; Rodrigues, Melanie; Galvez, Michael et al. (2018) Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice. Wound Repair Regen 26:300-305|
|Rodrigues, Melanie; Gurtner, Geoffrey (2017) Black, White, and Gray: Macrophages in Skin Repair and Disease. Curr Pathobiol Rep 5:333-342|
|Duscher, Dominik; Januszyk, Michael; Maan, Zeshaan N et al. (2017) Comparison of the Hydroxylase Inhibitor Dimethyloxalylglycine and the Iron Chelator Deferoxamine in Diabetic and Aged Wound Healing. Plast Reconstr Surg 139:695e-706e|
|Rennert, Robert C; Januszyk, Michael; Sorkin, Michael et al. (2016) Microfluidic single-cell transcriptional analysis rationally identifies novel surface marker profiles to enhance cell-based therapies. Nat Commun 7:11945|
|Rodrigues, Melanie; Wong, Victor W; Gurtner, Geoffrey C (2016) Finding a needle in a ""needlestack"". Cell Cycle 15:3331-3332|
|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|
|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; 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|
|Jung, Kenneth; Covington, Scott; Sen, Chandan K et al. (2016) Rapid identification of slow healing wounds. Wound Repair Regen 24:181-8|
Showing the most recent 10 out of 44 publications