Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression

Abstract

Mesenchymal stem cells (MSCs) are promising candidates for stem cell-based therapy in ischemic diseases. However, ischemic injury induces pathophysiological conditions, such as oxidative stress and inflammation, which diminish therapeutic efficacy of MSC-based therapy by reducing survival and functionality of transplanted MSCs. To overcome this problem, we explored the effects of melatonin on the proliferation, resistance to oxidative stress, and immunomodulatory properties of MSCs. Treatment with melatonin enhanced MSC proliferation and self-renewal via upregulation of cellular prion protein (PrP ) expression. Melatonin diminished the extent of MSC apoptosis in oxidative stress conditions by regulating the levels of apoptosis-associated proteins, such as BCL-2, BAX, PARP-1, and caspase-3, in a PrP -dependent manner. In addition, melatonin regulated the immunomodulatory effects of MSCs via the PrP -IDO axis. In a murine hind-limb ischemia model, melatonin-stimulated MSCs improved the blood flow perfusion, limb salvage, and vessel regeneration by lowering the extent of apoptosis of affected local cells and transplanted MSCs as well as by reducing infiltration of macrophages. These melatonin-mediated therapeutic effects were inhibited by silencing of PrP expression. Our findings for the first time indicate that melatonin promotes MSC functionality and enhances MSC-mediated neovascularization in ischemic tissues through the upregulation of PrP expression. In conclusion, melatonin-treated MSCs could provide a therapeutic strategy for vessel regeneration in ischemic disease, and the targeting of PrP levels may prove instrumental for MSC-based therapies.

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

“…Additionally, HSPA1L binds to OCT4 in cancer stem cells, resulting in maintenance of stemness (Lee et al, ). PrP C , the normal cellular prion protein, is a pivotal molecule with fundamental roles in self‐renewal, proliferation, and angiogenesis of stem/progenitor cells (Lee, Han, & Lee, ; Martin‐Lanneree et al, ; Martin‐Lanneree et al, ). Treatment with melatonin increases the function of MSCs through upregulation of PrP C , resulting in improvement of neovascularization in ischemic tissues (Lee, Han, & Lee, ).…”

“…PrP C , the normal cellular prion protein, is a pivotal molecule with fundamental roles in self‐renewal, proliferation, and angiogenesis of stem/progenitor cells (Lee, Han, & Lee, ; Martin‐Lanneree et al, ; Martin‐Lanneree et al, ). Treatment with melatonin increases the function of MSCs through upregulation of PrP C , resulting in improvement of neovascularization in ischemic tissues (Lee, Han, & Lee, ). In CKD, melatonin‐induced PrP C enhances mitochondrial function by binding to PINK1, leading to an increase in mitochondrial metabolism (Han et al, ).…”

“…Accumulating evidence has also shown that melatonin regulates apoptosis, autophagy, endoplasmic reticulum stress, and anti‐oxidant effects (Fernandez, Ordonez, Reiter, Gonzalez‐Gallego, & Mauriz, ; Garcia et al, ; Reiter et al, ). Furthermore, preclinical studies suggest that melatonin enhances the therapeutic potential of MSCs in myocardial infarction, chronic kidney disease (CKD), and hindlimb ischemia (Han et al, ; Lee, Han, & Lee, ; Lee, Jung, Oh, Yun, & Han, ). Our previous studies indicate that melatonin increases the regenerative potential of MSCs in ischemic disease and CKD through upregulation of cellular prion protein (PrP C ) which is involved in self‐renewal, differentiation, and angiogenesis in stem and/or progenitor cells (Doeppner et al, ; Han et al, ; Lee, Han, & Lee, ).…”

“…Furthermore, preclinical studies suggest that melatonin enhances the therapeutic potential of MSCs in myocardial infarction, chronic kidney disease (CKD), and hindlimb ischemia (Han et al, ; Lee, Han, & Lee, ; Lee, Jung, Oh, Yun, & Han, ). Our previous studies indicate that melatonin increases the regenerative potential of MSCs in ischemic disease and CKD through upregulation of cellular prion protein (PrP C ) which is involved in self‐renewal, differentiation, and angiogenesis in stem and/or progenitor cells (Doeppner et al, ; Han et al, ; Lee, Han, & Lee, ). However, the mechanism by which melatonin‐induced PrP C regulates the bioactivity of MSCs and protects them from stress and pathophysiological condition is still unclear.…”

Melatonin preconditioning is an effective strategy for mesenchymal stem cell‐based therapy for kidney disease

“…72,73 Incubation of MSCs with melatonin prior to transplantation has been confirmed to be able to induce an enhanced therapeutic outcome in multiple animal models, including myocardial infarction, cerebral ischemia and limb ischemia models. [74][75][76] In a broad sense, it was considered that melatonin itself could efficiently serve as an antioxidant and protect MSCs from oxidation injury by biologically eliminating free radicals. 66 In addition to receptor-independent pathways, the melatonin receptors MT1 and MT2 have also been found to be highly expressed on the surface of MSCs, indicating that melatonin may regulate the fate of MSCs in a receptor-dependent manner.…”