HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection

Abstract

Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ischemic tissue through the release of paracrine factors. The study of these factors is essential for understanding tissue repair and the development of new therapeutic approaches for regenerative medicine. We have recently shown that a novel factor secreted by MSCs, which we called HASF (Hypoxia and Akt induced Stem cell Factor), promotes cardiomyocyte proliferation. In this study we show that HASF has a cytoprotective effect on ischemia induced cardiomyocyte death. We assessed whether HASF could potentially be used as a therapeutic agent to prevent the damage associated with myocardial infarction. In vitro treatment of cardiomyocytes with HASF protein resulted in decreased apoptosis; tunel positive nuclei were fewer in number, caspase activation and mitochondrial pore opening were inhibited. Purified HASF protein was injected into the heart immediately following myocardial infarction. Heart function was found to be comparable to sham operated animals one month following injury and fibrosis was significantly reduced. In vivo and in vitro HASF activated protein kinase C ε (PKCε). Inhibition of PKCε blocked the HASF effect on apoptosis. Furthermore, the beneficial effects of HASF were lost in mice lacking PKCε. Collectively these results identify HASF as a protein of significant therapeutic potential, acting in part through PKCε.

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

“…Sfrp2 promotes the protection of cardiomyocytes by binding to the pro-apoptotic protein Wnt3a 29 . In contrast, HASF prevents cardiomyocyte cell-death through PKCε 31 . As noted in a recent editorial HASF has a number of novel features as a cytoprotective factor 136 .…”

“…Analysis of the heart tissue showed that HASF reduced the number of TUNEL positive nuclei as well as inhibiting caspase activation and mitochondrial pore opening. The cytoprotective effects of HASF were lost in mice lacking PKCε 31 .…”

Lens ER-stress response during cataract development in Mip-mutant mice

“…Hmox1 encodes heme oxygenase 1 (alias HSP37), an essential antioxidant heme-catabolism enzyme found to be cytoprotective against H 2 O 2 - induced oxidative-stress in lens epithelial cells (76). Trex1 encodes an ER-associated 3′-exonuclease implicated in suppressing innate immune responses (77) and 1190002N15Rik codes for a secreted Golgi protein (GoPro49) with cytoprotective properties (78). Taken together, the differential regulation of many genes unrelated to the UPR suggests that additional stress-response mechanisms may operate during Mip -related cataractogenesis.…”

Lens transcriptome profile during cataract development in Mip-null mice

“…Third, 1190002N15Rik was the only gene down-regulated in the Mip−/− lens and the Lop/+ lens at both P1 and P7 [24]. 1190002N15Rik encodes a secreted Golgi protein (GoPro49), also known as deleted in autism protein 1 homolog (DIA1) or hypoxia and Akt-induced stem cell factor (HASF), that possesses cytoprotective and anti-apoptotic properties; however, its role in the lens secretory pathway is unclear [38–40]. Finally, Hspb1 was moderately down-regulated in the Mip−/− lens at P1 and strongly down-regulated in the Lop/+ lens at P1 and P7.…”