Secreted factors from adipose tissue-derived mesenchymal stem cells suppress oxygen/glucose deprivation-induced cardiomyocyte cell death via furin/PCSK-like enzyme activity

Abstract

Clinical application of mesenchymal stem cells (MSCs) represents a potential novel therapy for currently intractable deteriorating diseases or traumatic injuries, including myocardial infarction. However, the molecular mechanisms of the therapeutic effects have not been precisely revealed. Herein, we report that conditioned media (CM) from rat adipose tissue-derived MSCs (ASCs) protected adult cardiomyocytes from oxygen/glucose deprivation (OGD)-induced cell death. We focused on furin/PCSK protease activity in ASC-CM because many therapeutic factors of MSCs and soluble cardioprotective factors include the PCSK cleavage site. We found that recombinant furin protected cardiomyocytes from OGD-induced cell death. The ASC-CM had potent furin/PCSK protease activity and the cardioprotective effect of the CM from ASCs in the OGD-assay was abolished by an inhibitor of the furin/PCSK-like enzyme. Microarray analysis and Western blot analysis showed PCSK5A, the secreted type of PCSK5, is the most abundantly secreted PCSK among 7 PCSK family members in ASC. Finally, knockdown of PCSK5A in ASCs decreased both the furin/PCSK protease activity and cardioprotective activity in the CM. These findings indicate an involvement of furin/PCSK-type protease(s) in the anti-ischemic activity of ASCs, and suggest a new mechanism of the therapeutic effect of MSCs.

Cardioprotective effects of rat adipose‑derived stem cells differ under normoxic/physioxic conditions and are�associated with paracrine factor secretion

“…For example, Sadat et al (34) reported that in an in vitro neonatal rat cardiomyocyte and ASC co-culture system, the anti-apoptotic effect of ASCs was observed under hypoxic conditions (a humidified atmosphere with 95% N 2 and 5% cO 2 gas mixture). Consistent with the results of the present study, a previous study demonstrated that the ASCs markedly suppressed oxygen deprivation-induced cardiomyocyte cell death, and the oxygen content in their cell culture condition was also set as 5% O 2 (35). To the best of our knowledge, the present study is the first report directly comparing the beneficial effects of ASCs under normoxia and physioxia on ventricular myocytes following oxidative stress.…”

Development and characterization of islet‐derived mesenchymal stem cells from clinical grade neonatal porcine cryopreserved islets

“…It has been reported that MSC co-culture/co-transplantation may enhance the therapeutic effect of cells of interest, such as cells of the liver 9 and myocardium. 48 Similarly, in pancreatic islets, the inhibition of apoptosis and enhancement of insulin secretory capacity of cultured Representative images (A). Colony-forming efficiency of cells (%) in CFU assay (B).…”