Metabolic regulation for the treatment of ischemic heart disease with stem cells and extracellular vesicles

Figures

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  Fig. 1. Substrate metabolic changes in cardiomyocytes in ischemic heart disease, treatment strategies and the role of stem cells in regulation of metabolism. Glucose, free fatty acids, β-hydroxybutyrate, and branched-chain amino acids enter cardiomyocytes and are metabolized to generate acetyl-CoA, which then enters the tricarboxylic acid cycle. This cycle generates reducing equivalents that fuel the electron transport chain, ultimately producing large amounts of ATP. Enhancing glucose, BCAA and ketone metabolism can provide cardioprotective effects in ischemic myocardium. Current research on stem cell therapy for ischemic heart disease mainly focuses on regulating glucose metabolism. Enzymes highlighted in blue-background boxes represent key regulatory points in the pathway. Red, blue, and purple arrows indicate pathological metabolic changes in IHD, stem cell-induced metabolic changes, and treatment strategies, respectively. Double-headed arrows represent bidirectional regulation.

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  Fig. 2. Regulatory mechanisms of mitochondrial metabolism and the role of stem cells. a Regulatory targets of mitochondrial oxidative stress. Keap1/Nrf2 alleviates oxidative stress by promoting the expression of antioxidant enzymes; b Regulatory targets of mitochondrial dynamics. Nrf1 activates mitochondrial biogenesis; MFN1/2 facilitates fusion, while Drp1 promotes fission; c Regulatory targets of mitophagy. ULK1 enhances autophagy. Notably, AMPK/PGC-1α plays a crucial regulatory role in these processes. d Stem cells contribute to reducing infarct size and restoring ATP levels by increasing mitochondrial biogenesis, promoting fusion, decreasing fission and mitigating oxidative stress. However, their impact on autophagy remains controversial. Red and blue arrows indicate pathological metabolic changes in IHD and stem cell-induced metabolic changes, respectively. Double-headed arrows represent bidirectional regulation.

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  Fig. 3. The impact of myocardial microenvironment on transplanted stem cells. The post-ischemic myocardial microenvironment (e.g., high-fat conditions, inflammation) compromises the survival and reparative function of transplanted stem cells by inducing metabolic disorders, loss of immunoprivilege, apoptosis, premature senescence, impaired angiogenic capacity and diminished proliferation/differentiation potential. Yellow arrows denote upregulation (↑) or downregulation (↓).

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  Fig. 4. Enhancing stem cell adaptation to the microenvironment. Prior to stem cell transplantation, preconditioning, gene modification or stem cell-based 3D tissue engineering can enhance survival and paracrine effects, thereby improving therapeutic outcomes. Key mechanisms include anti-inflammation, metabolic enhancement, anti-apoptosis, and anti-oxidative stress. Relevant references are indicated in the figure for detailed methodologies. Yellow arrows denote upregulation (↑) or downregulation (↓).