LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury

Abstract

Rationale Cell-based therapeutics have been extensively used for cardiac repair yet underperform due to inability of the donated cells to survive in near anoxia after cardiac injury. Cellular metabolism is linked to maintenance of cardiac stem cell (CSC) renewal, proliferation and survival. Ex vivo expansion alters (CSC) metabolism increasing reliance on oxygen dependent respiration. Whether promoting ‘metabolic flexibility’ in CSCs augments their ability to survive in near anoxia and repair the heart after injury remains untested. Objective Determine the effect of LIN28a induced metabolic flexibility on cardiac tissue derived stem like cell (CTSC) survival and repair after cardiac injury. Methods and results LIN28a expression coincides during heart development but is lost in adult CTSCs. Reintroduction of LIN28a in adult CTSC (CTSC- LIN ) increased proliferation, survival, expression of pluripotency genes and reduced senescence compared to control (CTSC- GFP ). Metabolomic analysis show glycolytic intermediates upregulated in CTSC- LIN together with increased lactate production, pyruvate kinase activity, glucose uptake, ECAR and expression of glycolytic enzymes compared to CTSC- GFP . Additionally, CTSC- LIN showed significantly reduced ROS generation and increase antioxidant markers. In response to H2O2 induced oxidative stress, CTSC- LIN showed increased survival and expression of glycolytic genes. LIN28a salutary effects on CTSCs were linked to PDK1/let-7 signaling pathway with loss of PDK1 or alteration of let-7 abrogating LIN28a effects. Following transplantation in the heart after myocardial infarction (MI), CTSC- LIN showed 6% survival rate at day 7 after injection compared to control cells together with increased proliferation and significant increase in cardiac structure and function 8 weeks after MI. Finally, CSTC-LIN showed enhanced ability to secrete paracrine factors under hypoxic conditions and ability to promote cardiomyocyte proliferation following ischemic cardiac injury. Conclusions LIN28a modification promotes metabolic flexibility in CTSCs enhancing proliferation and survival post transplantation including ability to repair the heart after myocardial injury.

LIN28 Family in Testis: Control of Cell Renewal, Maturation, Fertility and Aging

“…They found that LIN28AB enhances, while let-7 suppresses, aerobic glycolysis by targeting pyruvate dehydrogenase kinase 1 (PDK1), demonstrating a novel pathway to mediate aerobic glycolysis of cancer cells [116]. In accordance with a previous study, Yuko et al showed that LIN28A therapeutic effect on CTSCs was linked to the let-7/PDK1 signaling pathway [117]. Insight into the exact mechanisms of the LIN28/let-7 axis could enable the manipulation of cellular pluripotency and diseases such as diabetes and cancer.…”

“…Furthermore, CTSC-LIN had a significantly increased amount of antioxidant markers and reduced ROS generation compared to the control (CTSC-GFP). In addition, CSTC-LIN showed an increased ability to secrete pro-reparative paracrine factors under hypoxic conditions and promote cardiomyocyte proliferation and survival after ischemic cardiac injury [117]. In other words, LIN28 makes adult cardiac stem cells more metabolically flexible, significantly improving their chances of survival.…”

“…As some studies showed, impaired LIN28AB pathway can lead to several testicular disorders, among which are testicular germ cell tumors [22,110,111,140], hypogonadotropic hypogonadism [72], Klinefelter's syndrome [147], and other types of infertility [69,141,145,146]. There is growing evidence that targeting LIN28AB can be applied to stem-cell-based therapeutic approaches in various disorders [114,[155][156][157][158][159][160][161][162][163][164][165] or tissue injuries [38,117,167], indicating a possibility of targeting these paralogs in testicular disorder as well.…”

Endothelial cell-derived extracellular vesicles impair the angiogenic response of coronary artery endothelial cells

“…Expression of let-7 has been shown to increase with age in cardiac stem-like cells (CSLC). Following treatment of CSLC with a let-7 mimic, their proliferation was significantly reduced ( 52 ). Angiogenesis is repressed by overexpression of let-7 and by silencing of the let-7 target gene HMGA2 in EC ( 53 ).…”

Predicting Heart Cell Types by Using Transcriptome Profiles and a Machine Learning Method

“…ELAVL1 plays an important role in inhibiting hyperglycemia-induced cardiomyocyte pyroptosis and regulating ferroptosis in myocardial injury [51,52]. LIN28A is also implicated in various cardiac injuries or diseases [53,54]. NEAT1 (ENSG00000245532) produces a lncRNA that may act as a transcriptional regulator for numerous genes.…”