C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction

Abstract

Mesenchymal stromal cells (MSCs) transplantation offers an attractive alternative in myocardial infarctive therapy. However, poor cell engraftment and survival limit their restorative capacity. C1q/tumor necrosis factor-related protein-3 (CTRP3) inhibits reverse remodeling after myocardial infarction (MI) and was found to be secreted by MSCs in our preliminary experiments. We examined whether the overexpression of CTRP3 improved the survival of transplanted MSCs and augmented their efficacy on MI and whether silencing CTRP3 attenuated these effects. For gain-of-function analysis, MSCs overexpressing CTRP3 (LvC3-MSCs), control virus-transfected MSCs (LvNull-MSCs), MSCs alone, or phosphate-buffered saline (PBS) were injected into the peripheral areas of the infarction immediately after coronary artery ligation. For loss-of-function analysis, mice subjected to MI were randomized into groups and administered CTRP3-knockdown MSCs (LvshC3-MSCs), Lvshctrl-MSCs, MSCs, or PBS. Survival rates, cardiac function, and myocardial remodeling in mice were evaluated after 4 weeks. Injection of MSCs or LvNull-MSCs improved the left ventricular ejection fraction, inhibited cardiac fibrosis, and regulated cellular profiles of the infarction border zone 4 weeks after MI compared with those in the PBS group. Furthermore, overexpression of hCTRP3 promoted the efficacy of MSCs in the treatment of MI. However, knocking down CTRP3 impaired that. Coculture experiments confirmed that hCTRP3-enriched conditioned medium (CM) promoted MSCs migration and protected against H 2 O 2 -induced cell damage. Conversely, CM from C3 −/− MSCs (CTRP3 knock out) significantly reduced the migration and antioxidative effects of MSCs. CTRP3 protein alone promoted MSCs proliferation and migration by upregulating matrix metalloproteinase 9 (MMP9) and protecting against oxidation by increasing superoxide dismutase 2 (SOD2) and metallothionein 1/2 (MT1/2) expression; and these effects were blocked by pretreatment with the extracellular signal-regulated kinase (ERK1/2) inhibitor U0126. Overexpression of CTRP3 significantly improved the MSCs-based efficacy on MI by increasing cell survival and retention via a mechanism involving ERK1/2-MMP9 and ERK1/2-SOD2/MT1/2 signaling.

FNDC5/Irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction

“…Moreover, we also found that irisin/FNDC5 improved survivals of BM-MSCs under hypoxic condition. Recently, genetic modi cation has attracted great attention as a potential approach to improve the low viability of cells (8,(37)(38)(39) . For this reason, we up-regulated the FNDC5 expression in BM-MSCs, and transplanted FNDC5-MSCs into infarcted heart.…”

GDF11 inhibits cardiomyocyte pyroptosis and exerts cardioprotection in acute myocardial infarction mice by upregulation of transcription factor HOXA3

“…Acute myocardial infarction (MI) can lead to sudden cardiac death after prolonged ischemia, and can also dispose to heart failure with damaged left ventricle pump function 1,2 . MI is a primary risk factor of human lives that affects an increasing number of individuals worldwide 3,4 . During MI, a strong inflammatory response can bring adverse outcomes 5 .…”

FDNC5/Irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction

“…Moreover, we also found that irisin/FNDC5 improved survivals of BM-MSCs under hypoxic condition. Recently, genetic modification has attracted great attention as a potential approach to improve the low viability of cells (8,(35)(36)(37) . For this reason, we up-regulated the FNDC5 expression in BM-MSCs (FNDC5-MSCs), and transplanted FNDC5-MSCs into infarcted heart.…”