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.
|Suga, Hirotaka; Glotzbach, Jason P; Sorkin, Michael et al. (2014) Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation. Ann Plast Surg 72:234-41|
|Auerbach, Lauren J; DeClerk, Brittney K; Fathman, C Garrison et al. (2014) Poly-L-arginine topical lotion tested in a mouse model for frostbite injury. Wilderness Environ Med 25:160-5|
|Atashroo, David; Raphel, Jordan; Chung, Michael T et al. (2014) Studies in fat grafting: Part II. Effects of injection mechanics on material properties of fat. Plast Reconstr Surg 134:39-46|
|Wong, Victor W; Garg, Ravi K; Sorkin, Michael et al. (2014) Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing. Ann Surg 260:1138-46|
|Rennert, Robert C; Sorkin, Michael; Januszyk, Michael et al. (2014) Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations. Stem Cell Res Ther 5:79|
|Suga, Hirotaka; Rennert, Robert C; Rodrigues, Melanie et al. (2014) Tracking the elusive fibrocyte: identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing. Stem Cells 32:1347-60|
|Chung, Michael T; Paik, Kevin J; Atashroo, David A et al. (2014) Studies in fat grafting: Part I. Effects of injection technique on in vitro fat viability and in vivo volume retention. Plast Reconstr Surg 134:29-38|
|Rennert, Robert C; Rodrigues, Melanie; Wong, Victor W et al. (2013) Biological therapies for the treatment of cutaneous wounds: phase III and launched therapies. Expert Opin Biol Ther 13:1523-41|
|Auerbach, Lauren J; Galvez, Michael G; De Clerck, Brittney K et al. (2013) A novel mouse model for frostbite injury. Wilderness Environ Med 24:94-104|
|Wong, Victor W; Sorkin, Michael; Gurtner, Geoffrey C (2013) Enabling stem cell therapies for tissue repair: current and future challenges. Biotechnol Adv 31:744-51|
Showing the most recent 10 out of 20 publications