C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

Abstract

Background Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post myocardial infarction (MI). C1q/tumor necrosis factor–related protein-9 (CTRP9) is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. Methods Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were employed to uncover the molecular mechanisms of CTRP9. Results Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 vs. CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling and promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the above noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. Conclusion We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK/MMP-9 and ERK/Nrf2 signaling, and upregulation/secretion of anti-oxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway

“…Numerous studies have identified various pathological factors involved in the pathological process, including mitochondrial dysfunction, inflammatory response, endoplasmic reticulum stress, and oxidative stress . Despite extensive efforts having been put into the research of myocardial infarction and ischemic reperfusion injury, there still existed little effective treatment and intervention target …”

“…10 Despite extensive efforts having been put into the research of myocardial infarction and ischemic reperfusion injury, there still existed little effective treatment and intervention target. 11 Long non coding RNA (LncRNA) is a series of non coding RNA that is longer than 200 nt and is not coding protein. 12 LncRNA has been well-studied in different diseases, including cerebral stroke, 13 heart development, 14 and tumor development.…”

Interleukin‐11 regulates the fate of adipose‐derived mesenchymal stem cells via STAT3 signalling pathways

“…Adipose‐derived mesenchymal stem cells were isolated from inguinal subcutaneous adipose tissue as previously described . Briefly, adipose tissues were cut into small pieces in phosphate‐buffered saline (PBS) on ice.…”

“…Multiple studies utilizing MSCs have been conducted, being considered a promising treatment for ischaemic tissue injuries, such as hindlimb ischaemia and myocardial infarction . Due to the simplicity and reproducibility of the isolation process, adipose tissue has become an attractive source of MSCs for regenerative medicine . In recent years, multiple studies have been performed to use adipose‐derived mesenchymal stem cells (ADSCs) for the revascularization and tissue repair of ischaemic tissues.…”

Late‐onset renal hypertrophy and dysfunction in mice lacking CTRP1

“…Our efforts to identify novel regulators of metabolism have led to the identification and characterization of C1q/TNF-related proteins (CTRP1-15), secreted proteins of the C1q family conserved from fish to human. [6][7][8] In vivo animal studies highlight important metabolic, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] cardiovascular, [26][27][28][29][30][31][32][33][34][35][36] and inflammatory 12,13,[37][38][39][40] functions for multiple family members.…”