Cigarette Smoking Impairs Adipose Stromal Cell Vasculogenic Activity and Abrogates Potency to Ameliorate Ischemia

Author:

Barwinska Daria123ORCID,Traktuev Dmitry O.23456,Merfeld-Clauss Stephanie23456,Cook Todd G.2345,Lu Hongyan2345,Petrache Irina57,March Keith L.12345

Affiliation:

1. Department of Cellular and Integrative Physiology

2. Krannert Institute of Cardiology

3. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA

4. Division of Cardiology

5. Department of Medicine, Indiana University, Indianapolis, Indiana, USA

6. Center for Regenerative Medicine, Department of Medicine University of Florida, Gainesville, Florida, USA

7. Department of Medicine, National Jewish Health and University of Colorado, Denver, Colorado, USA

Abstract

Abstract Cigarette smoking (CS) adversely affects the physiologic function of endothelial progenitor, hematopoietic stem and progenitor cells. However, the effect of CS on the ability of adipose stem/stromal cells (ASC) to promote vasculogenesis and rescue perfusion in the context of ischemia is unknown. To evaluate this, ASC from nonsmokers (nCS-ASC) and smokers (CS-ASC), and their activity to promote perfusion in hindlimb ischemia models, as well as endothelial cell (EC) survival and vascular morphogenesis in vitro were assessed. While nCS-ASC improved perfusion in ischemic limbs, CS-ASC completely lost this therapeutic effect. In vitro vasculogenesis assays revealed that human CS-ASC and ASC from CS–exposed mice showed compromised support of EC morphogenesis into vascular tubes, and the CS-ASC secretome was less potent in supporting EC survival/proliferation. Comparative secretome analysis revealed that CS-ASC produced lower amounts of hepatocyte growth factor (HGF) and stromal cell-derived growth factor 1 (SDF-1). Conversely, CS-ASC secreted the angiostatic/pro-inflammatory factor Activin A, which was not detected in nCS-ASC conditioned media (CM). Furthermore, higher Activin A levels were measured in EC/CS-ASC cocultures than in EC/nCS-ASC cocultures. CS-ASC also responded to inflammatory cytokines with 5.2-fold increase in Activin A secretion, whereas nCS-ASC showed minimal Activin A induction. Supplementation of EC/CS-ASC cocultures with nCS-ASC CM or with recombinant vascular endothelial growth factor, HGF, or SDF-1 did not rescue vasculogenesis, whereas inhibition of Activin A expression or activity improved network formation up to the level found in EC/nCS-ASC cocultures. In conclusion, ASC of CS individuals manifest compromised in vitro vasculogenic activity as well as in vivo therapeutic activity.

Funder

AHA pre-doctoral award

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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