Endothelial progenitor cell dysfunction contributes to obesity-impaired wound healing in obese, non-diabetic humans and mice
Ida J Wagner, Robert J. Allen, Jr., Edward H. Davidson, Orlando Canizares, John P. Tutela, *Pierre B. Saadeh, *Stephen M. Warren
New York University, New York, NY
BACKGROUND: Obesity is an epidemic. One-third of the American population is overweight (BMI 25-29.9) and one-third is obese (BMI≥30). Surgeons have anecdotally appreciated impaired wound healing in obese patients, however, minimal investigation has been conducted in regards to obesity related wound healing. Bone marrow derived endothelial progenitor cells (EPCs) are responsible for approximately 35% of new blood vessel formation in healing wounds. We hypothesize that impaired wound healing in non-diabetic obesity is due to EPC dysfunction.
METHODS: Peripheral blood samples were obtained from non-diabetic obese patients (BMI > 30, n=20), and non-obese age matched controls (BMI<30, n=15). Subjects were free of conditions that affect EPC kinetics (new or chronic wounds, age > 60, smoking). EPCs were isolated and subjected to in vitro adhesion, migration and proliferation assays. To further investigate obesity related impaired wound healing in vivo, we wounded non-diabetic, obese mice (TallyHo/JngJ, n=15) and non-obese controls (n=15) using a stented wound model and photometrically measured time to closure over 21 days. In order to measure wound vascularization, CD31 staining of wound tissue was performed.
RESULTS: EPCs from obese subjects (EPC-Ob) did not adhere as well to collagen-coated slides as non-obese EPCs (EPC-n) (average 92 ± 20 cells per LPF vs. 137 ± 65 cells per LPF, p=0.05). EPC-Ob did not migrate as well as EPC-n (average 117 cells ± 21 per LPF vs. 393 ± 6 cells per LPF, p=0.02). EPC-Ob did not proliferate as frequently as EPC-n (average 179 ± 15 RFU vs. 305 ± 63 RFU, p=.0001). Wounds of control mice closed 50.2% at day 7, 92.7% at day 14 and 100% at day 21. Wounds of obese TallyHo mice were 40.8% closed at day 7, 79.1% at day 14 and 81.4% at day 21. Average vessel count per LPF was 453.7± 56.2 in control mice, and 276.2 ±41.1 in obese mice.
CONCLUSIONS: EPCs from non-diabetic obese humans evidenced impaired adhesion, migration and proliferation compared with EPCs from non-obese patients. Additionally, wound healing in obese, non-diabetic mice is delayed, and wound vascularity is decreased. Our data implicate EPC dysfunction as a possible mechanism behind impaired wound healing in obese humans and mice.