Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation.

BACKGROUND: Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models. METHODS: To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors. RESULTS: The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes. CONCLUSIONS: This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.

Scalable plasma and digital cognitive markers for diagnosis and prognosis of Alzheimer's disease and related dementias.

INTRODUCTION: With emergence of disease-modifying therapies, efficient diagnostic pathways are critically needed to identify treatment candidates, evaluate disease severity, and support prognosis. A combination of plasma biomarkers and brief digital cognitive assessments could provide a scalable alternative to current diagnostic work-up. METHODS: We examined the accuracy of plasma biomarkers and a 10-minute supervised tablet-based cognitive assessment (Tablet-based Cognitive Assessment Tool Brain Health Assessment [TabCAT-BHA]) in predicting amyloid ß positive (Aß+) status on positron emission tomography (PET), concurrent disease severity, and functional decline in 309 older adults with subjective cognitive impairment (n = 49), mild cognitive impairment (n = 159), and dementia (n = 101). RESULTS: Combination of plasma pTau181, Aß42/40, neurofilament light (NfL), and TabCAT-BHA was optimal for predicting Aß-PET positivity (AUC = 0.962). Whereas NfL and TabCAT-BHA optimally predicted concurrent disease severity, combining these with pTau181 and glial fibrillary acidic protein was most accurate in predicting functional decline. DISCUSSION: Combinations of plasma and digital cognitive markers show promise for scalable diagnosis and prognosis of ADRD. HIGHLIGHTS: The need for cost-efficient diagnostic and prognostic markers of AD is urgent. Plasma and digital cognitive markers provide complementary diagnostic contributions. Combination of these markers holds promise for scalable diagnosis and prognosis. Future validation in community cohorts is needed to inform clinical implementation.

Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring.

Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ. Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.

Transfer of Cardiac Mitochondria Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in a Preclinical Model of Ischemic Heart Disease.

BACKGROUND: The use of mesenchymal stem cells (MSCs) appears to be a promising therapeutic approach for cardiac repair after myocardial infarction. However, clinical trials have revealed the need to improve their therapeutic efficacy. Recent evidence demonstrated that mitochondria undergo spontaneous transfer from damaged cells to MSCs, resulting in the activation of the cytoprotective and pro-angiogenic functions of recipient MSCs. Based on these observations, we investigated whether the preconditioning of MSCs with mitochondria could optimize their therapeutic potential for ischemic heart disease. METHODS: Human MSCs were exposed to mitochondria isolated from human fetal cardiomyocytes. After 24 h, the effects of mitochondria preconditioning on the MSCs' function were analyzed both in vitro and in vivo. RESULTS: We found that cardiac mitochondria-preconditioning improved the proliferation and repair properties of MSCs in vitro. Mechanistically, cardiac mitochondria mediate their stimulatory effects through the production of reactive oxygen species, which trigger their own degradation in recipient MSCs. These effects were further confirmed in vivo, as the mitochondria preconditioning of MSCs potentiated their therapeutic efficacy on cardiac function following their engraftment into infarcted mouse hearts. CONCLUSIONS: The preconditioning of MSCs with the artificial transfer of cardiac mitochondria appears to be promising strategy to improve the efficacy of MSC-based cell therapy in ischemic heart disease.

Mitochondria on the move: Horizontal mitochondrial transfer in disease and health.

Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.

Intercellular Communication in the Brain through Tunneling Nanotubes.

Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine secretion and specialized structures ensuring physical contact between them. Among these intercellular specialized structures, tunneling nanotubes (TNTs) are now recognized as a means of cell-to-cell communication through the exchange of cellular cargo, controlled by a variety of biological triggers, as described here. Intercellular communication is fundamental to brain function. It allows the dialogue between the many cells, including neurons, astrocytes, oligodendrocytes, glial cells, microglia, necessary for the proper development and function of the brain. We highlight here the role of TNTs in connecting these cells, for the physiological functioning of the brain and in pathologies such as stroke, neurodegenerative diseases, and gliomas. Understanding these processes could pave the way for future therapies.

Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke.

AIM: Stroke results in long term serious disability that affect millions across the globe. Several clinical and preclinical studies have reinforced the therapeutic use of stem cells in stroke patients to enhance their quality of life. Previous studies from our lab have demonstrated that 1*105 allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) when given intraarterially (IA) render neuroprotection by modulating the expression of inflammasomes. Sirtuins are a class of important deacylases having a significant role in cellular functioning. Sirtuin-1 (SIRT-1) is an important enzyme essential for regulating cellular metabolism, which is reduced following an ischemic episode. The present study aims to unviel the role of MSCs in regulating the brain SIRT-1 levels following stroke and the involvement of SIRT-1 in regulating inflammasome signaling to reduce cellular apoptosis towards rendering neuroprotection. MATERIALS AND METHODS: 6 h post-reversible middle cerebral artery occlusion (MCAo), ovariectomized Sprague Dawley (SD) rats were infused intraarterially with 1*105 MSCs. 24 h after MCAo animals were examined for functional and behavioral outcomes. Brains were collected for assessing size of infarct and neuronal morphology. Molecular and immunofluroscence studies were also performed for assessing changes in gene and protein expressions. Extent of apoptosis was also determined in different groups. Inhibition study with SIRT-1 specific inhibitor EX-527 was also performed. RESULTS: A reduction in infarct size and improvement in motor functional and behavioral outcomes following infusion of MSCs IA at 6 h post-stroke was observed. Increase in average neuronal density and neuronal length was also seen. Increased expression of SIRT-1, BDNF and concomitant reduction in the expression of different inflammatory and apoptotic markers in the brain cortical regions were observed following MSCs treatment. CONCLUSION: Our study provides a preliminary evidence that post-stroke IA MSCs therapy regulates SIRT-1 to modulate NF-κB pathway to mitigate inflammasome signaling and cellular apoptosis. This study using IA approach for administering MSCs is highly relevant clinically. Our study is the first to report that neuroprotective effects of IA MSCs in rodent focal ischemia is mediated by SIRT-1 regulation of inflammasome signaling.

Transcriptional analysis of mouse wounds grafted with human mesenchymal stem cells and platelets.

Platelet preparations are commonly used in the clinic in combination with mesenchymal stem cells (MSCs) to improve their wound healing capacity and optimize their therapeutic efficacy following their delivery into diseased tissues. To investigate the mechanisms by which platelets enhance the repair properties of MSCs, we detail a protocol using a humanized mouse model for excisional wounds to study by reverse transcription real-time PCR whether human platelets alter the therapeutic efficacy of grafted human MSCs. For complete details on the use and execution of this protocol, please refer to Levoux et al. (2021).

Detecting Alzheimer's disease biomarkers with a brief tablet-based cognitive battery: sensitivity to Aß and tau PET.

BACKGROUND: ß-amyloid (Aß) and tau positron emission tomography (PET) detect the pathological changes that define Alzheimer's disease (AD) in living people. Cognitive measures sensitive to Aß and tau burden may help streamline identification of cases for confirmatory AD biomarker testing. METHODS: We examined the association of Brain Health Assessment (BHA) tablet-based cognitive measures with dichotomized Aß -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 Aß-, 97 Aß+). We also investigated the relationship between the BHA tests and regional patterns of tau-PET signal using voxel-wise regression analyses in a subsample of 60 Aß+ individuals with MCI or dementia. RESULTS: Favorites (associative memory), Match (executive functions and speed), and Everyday Cognition Scale scores were significantly associated with Aß positivity (area under the curve [AUC] = 0.75 [95% CI 0.66-0.85]). We found significant associations with tau-PET signal in mesial temporal regions for Favorites, frontoparietal regions for Match, and occipitoparietal regions for Line Orientation (visuospatial skills) in a subsample of individuals with MCI and dementia. CONCLUSION: The BHA measures are significantly associated with both Aß and regional tau in vivo imaging markers and could be used for the identification of patients with suspected AD pathology in clinical practice.

Platelets Facilitate the Wound-Healing Capability of Mesenchymal Stem Cells by Mitochondrial Transfer and Metabolic Reprogramming.

Platelets are known to enhance the wound-healing activity of mesenchymal stem cells (MSCs). However, the mechanism by which platelets improve the therapeutic potential of MSCs has not been elucidated. Here, we provide evidence that, upon their activation, platelets transfer respiratory-competent mitochondria to MSCs primarily via dynamin-dependent clathrin-mediated endocytosis. We found that this process enhances the therapeutic efficacy of MSCs following their engraftment in several mouse models of tissue injury, including full-thickness cutaneous wound and dystrophic skeletal muscle. By combining in vitro and in vivo experiments, we demonstrate that platelet-derived mitochondria promote the pro-angiogenic activity of MSCs via their metabolic remodeling. Notably, we show that activation of the de novo fatty acid synthesis pathway is required for increased secretion of pro-angiogenic factors by platelet-preconditioned MSCs. These results reveal a new mechanism by which platelets potentiate MSC properties and underline the importance of testing platelet mitochondria quality prior to their clinical use.

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer.

Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

Platelet-Rich Plasma Improves the Wound Healing Potential of Mesenchymal Stem Cells through Paracrine and Metabolism Alterations.

Chronic and acute nonhealing wounds represent a major public health problem, and replacement of cutaneous lesions by the newly regenerated skin is challenging. Mesenchymal stem cells (MSC) and platelet-rich plasma (PRP) were separately tested in the attempt to regenerate the lost skin. However, these treatments often remained inefficient to achieve complete wound healing. Additional studies suggested that PRP could be used in combination with MSC to improve the cell therapy efficacy for tissue repair. However, systematic studies related to the effects of PRP on MSC properties and their ability to rebuild skin barrier are lacking. We evaluated in a mouse exhibiting 4 full-thickness wounds, the skin repair ability of a treatment combining human adipose-derived MSC and human PRP by comparison to treatment with saline solution, PRP alone, or MSC alone. Wound healing in these animals was measured at day 3, day 7, and day 10. In addition, we examined in vitro and in vivo whether PRP alters in MSC their proangiogenic properties, their survival, and their proliferation. We showed that PRP improved the efficacy of engrafted MSC to replace lost skin in mice by accelerating the wound healing processes and ameliorating the elasticity of the newly regenerated skin. In addition, we found that PRP treatment stimulated in vitro, in a dose-dependent manner, the proangiogenic potential of MSC through enhanced secretion of soluble factors like VEGF and SDF-1. Moreover, PRP treatment ameliorated the survival and activated the proliferation of in vitro cultured MSC and that these effects were accompanied by an alteration of the MSC energetic metabolism including oxygen consumption rate and mitochondrial ATP production. Similar observations were found in vivo following combined administration of PRP and MSC into mouse wounds. In conclusion, our study strengthens that the use of PRP in combination with MSC might be a safe alternative to aid wound healing.

Endoplasmic reticulum-mitochondria crosstalk: from junction to function across neurological disorders.

The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER-mitochondrial interconnections form specific microdomains, called mitochondria-associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER-mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER-mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER-mitochondrial interconnections in neurological disorders.

Efficacy of Autologous Platelet Concentrates as Adjuvant Therapy to Surgical Excision in the Treatment of Keloid Scars Refractory to Conventional Treatments: A Pilot Prospective Study.

BACKGROUND: After conventional treatments, keloid scars show varying degrees of recurrence. The aim of this study was to assess the efficacy and safety of platelet-rich plasma in the treatment of postoperative keloid scars refractory to conventional treatments. METHODS: This pilot prospective study was conducted in 17 patients with keloid scars who did not respond to 4 injections of cortisone or radiotherapy after extralesional resection of keloid. Platelet-rich plasma was injected intraoperatively and then 3 times with a 1-month interval. The primary end point was the complete remission of keloid scars 2 years posttreatment. Scar pruritus severity was scored before and after treatment. The study protocol was approved by the ethics committee and authorized by the French National Agency. This trial was registered at ClinicalTrials.gov, identifier NCT02922972. RESULTS: Nine keloid scars (53%) were completely resolved at 2 years, and 5 (29%) completely relapsed after treatment. Pruritus severity score was significantly lower at 2 years compared with baseline (1.33 ± 0.97 before treatment and 0.40 ± 0.63 at 2 years, P < 0.003). The mean Vancouver Scar Scale score significantly improved (8.18 ± 2.38 before treatment and 3.82 ± 1.98 at 2 years, P < 0.001). CONCLUSIONS: Injecting platelet-rich plasma is an effective and safe method as adjunctive therapy to resection for treating keloid scars refractory to conventional therapy.

Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury.

Mitochondria are crucial organelles that not only regulate the energy metabolism, but also the survival and fate of eukaryotic cells. Mitochondria were recently discovered to be able to translocate from one cell to the other. This phenomenon was observed in vitro and in vivo, both in physiological and pathophysiological conditions including tissue injury and cancer. Mitochondria trafficking was found to exert prominent biological functions. In particular, several studies pointed out that this process governs some of the therapeutic effects of mesenchymal stem cells (MSCs). In this review, we give an overview of the current knowledge on MSC-dependent intercellular mitochondria trafficking and further discuss the recent findings on the intercellular mitochondria transfer between differentiated and mesenchymal stem cells, their biological significance and the mechanisms underlying this process.

Should platelet-rich plasma be activated in fat grafts? An animal study.

BACKGROUND: The adjunction of platelet-rich plasma with graft fat has been the subject of a few clinical trials which have demonstrated its value in adipocyte survival. The aim of this study was to assess the different efficacies between activated and non-activated PRP on adipose cells in vitro and for adipose tissue graft survival in vivo. METHODS: The in vitro study assessed the effects of PRP on both the proliferation and adipocyte differentiation of adipose cells. For the in vivo study, 8 nude rats received 3 human fat injections as follows: 0.8 mL of fat + 0.2 mL of normal saline; 0.8 mL of fat + 0.2 mL of non-activated PRP; and 0.8 mL of fat + 0.2 mL of PRP activated with calcium chloride (CaCl2). The quantitative assessment of adipocyte survival was implemented after 3 months using histomorphometric analysis. Histological and immunohistochemical analysis were also performed to evaluate angiogenesis, inflammation and quality of adipocytes in the grafted tissue. RESULTS: We showed that activated PRP stimulated, in vitro, proliferation and differentiation of adipose cells. In vivo experiments indicated that CaCl2-activated PRP was more efficient than non-activated to prolong the survival of fat grafts in nude rats. The mean percentage areas occupied by viable adipocytes in the PRP-free group, non-activated PRP group and activated PRP group were 13%, 14% and 24% (p = 0.05%), respectively. Histological and immunohistochemical analysis revealed protective effect of activated PRP on inflammation and adipocyte death. CONCLUSION: This study showed that activation by CaCl2 improves the beneficial effects of PRP for fat graft maintenance.

Intracavernous Injections of Bone Marrow Mononucleated Cells for Postradical Prostatectomy Erectile Dysfunction: Final Results of the INSTIN Clinical Trial.

We recently reported stage I of a phase 1/2 clinical trial of cell therapy to treat postradical prostatectomy erectile dysfunction (INSTIN, INtra-cavernous STem-cell INjection clinical trial, NCT01089387). In this first stage, four doses of intracavernous autologous bone marrow mononuclear cells (BM-MNCs) were tested in 12 patients. Here, we report the results of stage II, in which six additional patients received the optimal dose identified in stage I (109 BM-MNCs), and the long-term results in the 12 patients included in stage I. The objectives were to assess the safety and efficacy of this new treatment. In stage II, no patients had side effects, and the erectile function improvements were similar to those seen in stage I: after 6 months, significant improvements versus baseline were noted in International Index of Erectile Function-15 intercourse satisfaction (7.8±3.1 vs 2.2±3.4, p=0.033) and erectile function (18±8.3 vs 3.7±4.1, p=0.035) domains. In stage I patients, after a mean follow-up of 62.1±11.7 mo, there were no prostate cancer recurrences, and erectile function scores were somewhat lower compared with the 1-yr time point. These findings suggest that intracavernous BM-MNC injections are safe and improve erectile function. The decline in erectile function over time suggests a need for assessing repeated injections. PATIENT SUMMARY: We report a phase 1/2 pilot clinical trial of cell therapy consisting in intracavernous injection of bone marrow mononuclear cells to treat postradical prostatectomy erectile dysfunction. Erectile function was improved after 6 mo in the patients given 1×109 cells. No serious side effects (life threatening or requiring hospitalisation) occurred after a mean follow-up of 62.1 mo in the first 12 patients.

Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.