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

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. Stem Cells 2018;36:856-867.

Adipose Stem Cells in Regenerative Medicine: Looking Forward

“…Nevertheless, there are still many hoops to jump ahead and a long way to get these therapies to move from clinical trials to FDA-approved treatments. One of the limitations for the usage of ASCs in regenerative medicine is the donor’s age, body mass index (BMI) and health conditions (underlying disease or comorbidities), which might result in reduced immunomodulatory abilities of main regulatory factors ( Strong et al, 2013 ; Barwinska et al, 2018 ). Thus, ASCs should be fully characterizing and thoroughly screened for in vitro aging and inflammatory markers that might affect their regenerative abilities and hinder their usage in clinical application.…”

Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential

“…A study carried out by Barwinska et al (8) showed that ASCs isolated from smokers expressed lower anti-inflammatory and angiogenic factors but higher expression of the pro-inflammatory factor Activin A compared with ASCs obtained from nonsmokers. Thus the therapeutic potential, as well as the vasculogenic ability, of ASCs is compromised in smokers, as demonstrated both in vitro and in vivo models (8).…”

Effects of Nicotine on the Translation of Stem Cell Therapy

“…utilized a mouse HLI model to show that MSCs derived from smokers had significantly dampened angiogenesis, compared to nonsmokers [35]. In vitro experiments from the same study suggest a possible molecular mechanism involving activin A, whereby activin A diminishes secretion of hepatocyte growth factor and stromal derived factor-1 (Table 1).…”