Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury

Abstract

Damage to endothelial cells contributes to acute kidney injury (AKI) by causing impaired perfusion, while the permanent loss of the capillary network following AKI has been suggested to promote chronic kidney disease. Therefore, strategies to protect renal vasculature may impact both short‐term recovery and long‐term functional preservation post‐AKI. Human adipose stromal cells (hASCs) possess pro‐angiogenic and anti‐inflammatory properties and therefore have been tested as a therapeutic agent to treat ischaemic conditions. This study evaluated hASC potential to facilitate recovery from AKI with specific attention to capillary preservation and inflammation. Male Sprague Dawley rats were subjected to bilateral ischaemia/reperfusion and allowed to recover for either two or seven days. At the time of reperfusion, hASCs or vehicle was injected into the suprarenal abdominal aorta. hASC‐treated rats had significantly greater survival compared to vehicle‐treated rats (88.7% versus 69.3%). hASC treatment showed hastened recovery as demonstrated by lower creatinine levels at 48 hrs, while tubular damage was significantly reduced at 48 hrs. hASC treatment resulted in a significant decrease in total T cell and Th17 cell infiltration into injured kidneys at 2 days post‐AKI, but an increase in accumulation of regulatory T cells. By day 7, hASC‐treated rats showed significantly attenuated capillary rarefaction in the cortex (15% versus 5%) and outer medulla (36% versus 18%) compared to vehicle‐treated rats as well as reduced accumulation of interstitial alpha‐smooth muscle actin‐positive myofibroblasts. These results suggest for the first time that hASCs improve recovery from I/R‐induced injury by mechanisms that contribute to decrease in inflammation and preservation of peritubular capillaries.

Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury

“…Recent studies from our own laboratory have shown that Th17 cells represent the most prominent T-helper population induced by renal I/R in rats (32). Moreover, Th17 infiltration is enhanced in vitamin D-deficient rats, which exacerbates AKI (20), while Th17 cell infiltration is reduced by the administration of adipose-derived stromal cells which attenuate AKI (25). A potential role for Th17 cells in the pathogenesis of AKI is supported by studies in which mice lacking the IL-17A gene were protected against the development of AKI induced by cisplatin (17,32).…”

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

“…Furthermore, Activin A promotes macrophage polarization toward a pro-inflammatory M1 phenotype [78]. Accordingly, we hypothesize that while nCS-ASC, after systemic injection, can down-modulate inflammatory pathways [79], CS-ASC, through an increase in Activin A secretion, may mediate a pro-inflammatory effect, which consequently abolishes their therapeutic potential.…”

Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patients

“…Prior studies in diabetic PAD population had smaller but similar or smaller sample sizes [n=1(Smadja) 32 ; n=3 (Gremmels) 13 ; n=4 (Brewster) 12 ], making this the largest study to date. While the sample size for human cells is not always included in manuscripts similar to ours 33–35 , there are a number of publications that have sample sizes similar to ours 36–38 . Thus, we think our sample size is a reasonable number but do not exclude the possibility that small differences between the BM and ATD-dMSCs could be identified with a larger sample size.…”