Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

Mesenchymal stem cells (MSCs) are among the most frequently used cell type for regenerative medicine. A large number of studies have shown the beneficial effects of MSC-based therapies to treat different pathologies, including neurological disorders, cardiac ischemia, diabetes, and bone and cartilage diseases. However, the therapeutic potential of MSCs in cancer is still controversial. While some studies indicate that MSCs may contribute to cancer pathogenesis, emerging data reported the suppressive effects of MSCs on cancer cells. Because of this reality, a sustained effort to understand when MSCs promote or suppress tumor development is needed before planning a MSC-based therapy for cancer. Herein, we provide an overview on the therapeutic application of MSCs for regenerative medicine and the processes that orchestrates tissue repair, with a special emphasis placed on cancer, including central nervous system tumors. Furthermore, we will discuss the current evidence regarding the double-edged sword of MSCs in oncological treatment and the latest advances in MSC-based anti-cancer agent delivery systems.Junta de Andalucía PI-0272-2017Ministerio de Ciencia, Innovación y Universdad CD16/00118, CP19/00046, PI16/00259, BFU2017-83588-P, CP14/00105, PI18/01590, PI17/02104, PIC18/0010, IC19/0052Juvenile Diabetes Research Foundation (USA) 2-SRA-2019-837-S-BFundación Española para la Ciencia y la Tecnología 2018-00023

Bottlenecks in the efficient use of advanced therapy medicinal products based on mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) have been established as promising candidate sources of universal donor cells for cell therapy due to their contributions to tissue and organ homeostasis, repair, and support by self-renewal and multidifferentiation, as well as by their anti-inflammatory, antiproliferative, immunomodulatory, trophic, and proangiogenic properties. Various diseases have been treated by MSCs in animal models. Additionally, hundreds of clinical trials related to the potential benefits of MSCs are in progress. However, although all MSCs are considered suitable to exert these functions, dissimilarities have been found among MSCs derived from different tissues. The same levels of efficacy and desired outcomes have not always been achieved in the diverse studies that have been performed thus far. Moreover, autologous MSCs can be affected by the disease status of patients, compromising their use. Therefore, collecting information regarding the characteristics of MSCs obtained from different sources and the influence of the host (patient) medical conditions on MSCs is important for assuring the safety and efficacy of cell-based therapies. This review provides relevant information regarding factors to consider for the clinical application of MSCs.The authors are supported by the Fundacion Progreso y ´ Salud, Consejer´ıa de Salud, Junta de Andaluc´ıa; FEDER cofunded grants from Consejer´ıa de Innovacion Ciencia y ´ Empresa, Junta de Andaluc´ıa (Grants CTS-6505; INP-2011- 1615-900000); FEDER cofunded grants from Instituto de Salud Carlos III (Red TerCel-Grant RD12/0019/0028; PI10/ 00964 and PI14/01015) and the Ministry of Health and Consumer Affairs (Advanced Therapies Program Grant TRA- 120); SUDOE Program-BIOREG (Regenerative Medicine Network-SOE3/P1/E750) and ACTION Cost (European Cooperation in Science and Technology-BM1305). Support from FSED and FAID allowed access to databanks. CIBERDEM is an initiative of the Instituto de Salud Carlos IIIPeer Reviewe

Editorial: Mesenchymal stromal cell therapy for regenerative medicine

Mesenchymal stromal/stem cell (MSC) therapies are increasingly explored as novel regenerative and immunomodulatory approaches to treat or prevent diseases (Pittenger et al., 2019; Hmadcha et al., 2020; Moll et al., 2020b; Ringdén et al., 2022). These cells exhibit potent paracrine properties that can modulate host immune responses, lower inflammation, and orchestrate endogenous tissue repair, at both the local and the systemic level through multiple pathways (Singer and Caplan, 2011; Doorn et al., 2012). MSCs possess tropism toward damaged and inflamed tissues, where they can engraft short-term and exert their therapeutic effects by both direct and indirect mechanisms (Doorn et al., 2012; Galipeau and Sensebe, 2018; Soria et al., 2019). MSC products can be prepared from multiple sources (Moll et al., 2019, 2022), rapidly expanded and biobanked for clinical application. All these advantages make this cell type a versatile tool in regenerative medicine. The goal of our Research Topic is to highlight the latest advances in applications of MSCs for the treatment of a variety of diseases and their modes of action (MoA). A better understanding of the mechanisms underlying the therapeutic effect of MSCs can provide crucial insight into innovative strategies to enhance their effectiveness in clinical application (Singer and Caplan, 2011; Doorn et al., 2012; Galipeau and Sensebe, 2018; Moll et al., 2019, 2020b, 2022; Pittenger et al., 2019; Ringdén et al., 2022). The subjects covered within this Research Topic include: (a) Therapeutic application of MSCs for major clinical indications, (b) Cellular and molecular mechanisms underlying therapeutic effects of MSCs, and (c) Strategies for enhancement of the therapeutic effects of MSCs and their products. Here, we summarize the 37 manuscripts that were submitted to this Research Topic (Figure 1)

Impact of transient down-regulation of DREAM in human embryonic stem cell pluripotency: The role of DREAM in the maintenance of hESCs

Little is knownabout the functions of downstreamregulatory element antagonist modulator (DREAM) inembryonic stem cells (ESCs). However, DREAM interacts with cAMP response element-binding protein (CREB) in a Ca2+-dependent manner, preventing CREB binding protein (CBP) recruitment. Furthermore, CREB and CBP are involved in maintaining ESC self-renewal and pluripotency. However, a previous knockout study revealed the protective function of DREAMdepletion in brain aging degeneration and that aging is accompanied by a progressive decline in stem cells (SCs) function. Interestingly, we found that DREAM is expressed in different cell types, including human ESCs (hESCs), human adipose-derived stromal cells (hASCs), human bone marrow-derived stromal cells (hBMSCs), and human newborn foreskin fibroblasts (hFFs), and that transitory inhibition of DREAMin hESCs reduces their pluripotency, increasing differentiation.We stipulate that these changes are partly mediated by increased CREB transcriptional activity. Overall, our data indicates that DREAMacts in the regulation of hESC pluripotency and could be a target to promote or prevent differentiation in embryonic cells.Junta de Andalucía, Consejería de Innovación Ciencia y Empresa, FEDER CTS-6505; INP-2011- 1615-900000; P10-CVI-6095Instituto de Salud Carlos III, FEDER RD12/0019/0028; PI10/00964; PI14/0101

miR-7 Modulates hESC Differentiation into Insulin-Producing Beta-like Cells and Contributes to Cell Maturation

Human pluripotent stem cells retain the extraordinary capacity to differentiate into pancreatic beta cells. For this particular lineage, more effort is still required to stress the importance of developing an efficient, reproducible, easy, and cost-effective differentiation protocol to obtain more mature, homogeneous, and functional insulin-secreting cells. In addition, microRNAs (miRNAs) have emerged as a class of small non-coding RNAs that regulate many cellular processes, including pancreatic differentiation. Some miRNAs are known to be preferentially expressed in islets. Of note, miR-375 and miR-7 are two of the most abundant pancreatic miRNAs, and they are necessary for proper pancreatic islet development. Here we provide new insight into specific miRNAs involved in pancreatic differentiation. We found that miR-7 is differentially expressed during the differentiation of human embryonic stem cells (hESCs) into a beta cell-like phenotype and that its modulation plays an important role in generating mature pancreatic beta cells. This strategy may be exploited to optimize the potential for in vitro differentiation of hESCs into insulin-producing beta-like cells for use in preclinical studies and future clinical applications as well as the prospective uses of miRNAs to improve this process.Spanish Ministry of Economy and Competitiveness BFU2016-74932-C2 BFU2013-45564-C2FEDER Funds PI-0272-2017Andalusian Regional Ministry of Health PI-0272-2017European Cooperation in Science and Technology BM1305Spanish Ministry of Economy, Industry and Competitiveness CD16/00118Spanish Institute of Health Carlos III PI16/00259 PI17/02104 RD16/0011/0034 CD16/0011

The generation of oligodendroglial cells is preserved in the rostral migratory stream during aging.

The subventricular zone (SVZ) is the largest source of newly generated cells in the adult mammalian brain. SVZ-derived neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into mature neurons. Additionally, a small proportion of SVZ-derived cells contribute to the generation of myelinating oligodendrocytes. The production of new cells in the SVZ decreases during aging, affecting the incorporation of new neurons into the OB. However, the age-related changes that occur across the RMS are not fully understood. In this study we evaluate how aging affects the cellular organization of migrating neuroblast chains, the proliferation, and the fate of the newly generated cells in the SVZ-OB system. By using electron microscopy and immunostaining, we found that the RMS path becomes discontinuous and its cytoarchitecture is disorganized in aged mice (24-month-old mice). Subsequently, OB neurogenesis was impaired in the aged brain while the production of oligodendrocytes was not compromised. These findings provide new insight into oligodendrocyte preservation throughout life. Further exploration of this matter could help the development of new strategies to prevent neurological disorders associated with senescence

Role of mesenchymal stem cells in the remodeling of the extracellular matrix in glioblastoma

Motivation: Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. Patients who suffer from this malignancy have a median survival rate of approximately 12 months. Current treatments for GBM are surgery, radiotherapy, and chemotherapy (1), but these treatments do not offer a definitive solution. In this context, the cell therapy based on mesenchymal stem cells (MSCs) has emerged as a promising alternative to improve the survival of patients (2). Our study aims to investigate the underlying mechanisms by which MSCs could exert beneficial effects in GBM, paying special attention to the extracellular matrix remodeling. Methods: All in vitro and in vivo studies were performed using three experimental groups: U87 glioma cells (U87), U87 glioma cells in the presence of MSCs (U87+MSC), and U87 glioma cells in the presence of MSCs previously pretreated with a substance that improves their therapeutic properties (U87+MSCpret). First, using paraffin-embedding tissuse sections of tumors that were subcutaneously grown in immunosuppressed mice (n=5), we performed a Sirius Red staining to quantify the collagen fibers content. Second, using the transwell coculture system (3),  we conducted an RNA-Seq analysis to evaluate the expression levels of genes involved in extracellular matrix remodeling in the U87 glioma cells of each experimental group (n=3). RT-qPCR was performed to validate the RNA-Seq results (n=3). Values of p <0.05 were considered statistically significant. Results: The quantification of the collagen deposition in subcutaneous tumors showed a tendency to decrease in the U87+MSCpret group. In the RNA-Seq analysis, we obtained a list of extracellular matrix-related genes with a significant differential expression (e.g. Mmp28, Hyal1, Col24a1, Cemip, Eln). RT-qPCR results showed a tendency to reduce the expression of genes related to the remodeling of the extracellular matrix, such as Mmp9, Mmp2, Timp1, Timp2 or Tgf-β, in the U87+MSCpret group. Of note, this reduction in the expression levels became significant for Timp1 (p<0.05). Conclusions: Pretreated MSCs prevent the accumulation of collagen in the GMB using in vivo models, which is associated with less invasive tumors. In vitro, we identified that the expression of extracellular matrix proteins tended to decrease in GBM cells when they were co-cultured with pretreated MSCs, suggesting that these cells may reduce tumorigenesis by altering extracellular matrix remodeling

Human Mesenchymal Stem Cells Prevent Neurological Complications of Radiotherapy

Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer patients. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cells (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. This intervention confers protection against inflammation, oxidative stress, and neuronal loss. hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in irradiated brains. Furthermore, hMSC treatment did not compromise the survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as a non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor patients

Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients

Human induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors

Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

19 Páginas.-- 7 FigurasATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.This work was funded by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, co-funded by Fondos FEDER (PI15/00134, PI18/01590, CPII19/00023 to A.M.M.) and the Ministerio de Ciencia e Innovación (PID2021-123965OB-100 to A.M.M.). A.M.M. is funded by the Junta de Andalucía P20_00480, the Spanish Society of Diabetes, and CSIC 202220I059. M.S.K. is funded by the Nordea Foundation (#02-2017-1749), the Novo Nordisk Foundation (#NNF17OC0027812), the Neye Foundation, the Lundbeck Foundation (#R324-2019-1492), the Ministry of Higher Education and Science of Denmark (#0238-00003B). V.C.G. is funded by the Instituto de Salud Carlos III (CP19/00046), co-funded by FEDER. F.M. is funded by the CIBERDEM of the Instituto de Salud Carlos III. A.M.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge the support of the group of basic research on diabetes of the Spanish Society of Diabetes.Peer reviewe