Diabetes impairs the micro- and macrocirculation, leading to limb ischemia and chronic non-healing wounds. Conventional methods of treating diabetes, such as insulin and oral hypoglycemic agents, can control the disease but do not prevent diabetic complications. This highlights the need for new approaches to therapy. Over the past decade, we defined many of the molecular and cellular perturbations that underlie impaired diabetic wound healing, including defects in both the wound microenvironment and progenitor cell function that contribute to the pathogenesis of diabetic complications. To understand the effects of diabetes on progenitor cell populations with more clarity, we have also developed novel transgenic murine models and single cell gene expression analyses. In this proposal, we will define the discrete defects in progenitor subpopulations are impacted by diabetes and determine whether they are reversible. We will extend this work therapeutically by using cell-based approaches to normalize these defects to treat or reverse diabetic complications including wound healing. To do this, we will utilize lineage tracing and single-cell transcriptional analysis to define the effect of diabetes on progenitor cell subsets and heterogeneity (Specific Aim 1). We will then determine whether diabetes-induced defects in stem/progenitor cell pools are reversible (Specific Aim 2), which will clarify the potential of diabetic cells as a source for cell therapies. Finally, we will use this experimental information t reverse diabetes-induced defects in stem/progenitor cell populations and treat diabetic complications (Specific Aim 3). Taken together, our approach of identifying subpopulation deficits in diabetes and treating these dysfunctions with enriched progenitor subsets will permit highly specific and effective cellular therapy, a much needed alternative to existing treatments for diabetic complications.

Public Health Relevance

Diabetes and its associated co-morbidities are a major public health concern affecting nearly 10% of the US population. Wound healing is markedly impaired in the diabetic state which can be attributed in part to progenitor cell dysfunction. To understand the effects of diabetes on progenitor cell populations with greater clarity, we have developed transgenic murine models and single cell gene expression analyses to identify critical alterations in rare cell subpopulations. It is our fundamental hypothesis that diabetes alters the 'cellular ecology' of heterogeneous cell populations involved in healing, and that normalization of those cell subpopulations through cell based therapy can reverse this diabetic complication. This proposal focuses on definitely identifying these altered subpopulations in diabetic mice and humans, and translating these findings to develop clinical strategies to restore depleted cell subsets in order to treat diabetic complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074095-13
Application #
9252451
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2005-09-30
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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

Showing the most recent 10 out of 37 publications