Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrP^C‐dependent enhancement of the mitochondrial function

Abstract

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H2O2 to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H2O2 and associated excessive senescence. The latter was mediated by PrPC‐dependent mitochondrial functional enhancement; melatonin upregulated PrPC, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H2O2‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrPC and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs.

Melatonin‐stimulated exosomes enhance the regenerative potential of chronic kidney disease‐derived mesenchymal stem/stromal cells via cellular prion proteins

“…CKD‐induced uremic toxins, such as indoxyl sulfate and p‐cresol, hamper the biological activities of MSCs and lead to cardiovascular disease, weakened bones, malfunctioning central nervous system, and improper inflammation in patients . The regenerative potential of CKD‐MSCs is also suppressed in a murine ischemic injury . Consistent with these findings, our results have shown that biological functions like senescence, proliferation, and mitochondrial activity were significantly decreased in CKD‐MSCs and treatment with MT exosomes drastically improved these CKD‐mediated pathophysiological conditions.…”

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

“…Previous studies have shown that PrP C binds to PTEN‐induced kinase 1 (PINK1) which regulates mitochondrial quality control through the mitophagy process (Han et al, ; Yoon et al, ). To understand whether melatonin stabilizes the expression of PrP C for recruitment into mitochondria in senescent MSCs via chaperone protein, we focused on HSPA1L, which is a member of the heat shock protein 70 (HSP70) family and contributes to stabilization of protein, signal transduction, and protein homeostasis (Mayer & Bukau, ).…”

“…A variety of studies have shown that melatonin protects against senescence associated with oxidative stress (Zhou et al, ), neurodegeneration (Caballero et al, ), and CKD (Han et al, ). Melatonin rescues oxidative stress‐induced premature senescence in MSCs through attenuation of p‐p38, inhibition of p16 INK4α , and augmentation of SIRT1 (Zhou 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.…”