Mesenchymal stem cells (MSC) are present in all organs and tissues. Several studies have shown the therapeutic potential effect of MSC or their derived products. However, the functional heterogeneity of MSC constitutes an important barrier for transferring these capabilities to the clinic. MSC heterogeneity depends on their origin (biological niche) or the conditions of potential donors (age, diseases or unknown factors). It is accepted that many culture conditions of the artificial niche to which they are subjected, such as O 2 tension, substrate and extracellular matrix cues, inflammatory stimuli or genetic manipulations can influence their resulting phenotype. Therefore, to attain a more personalized and precise medicine, a correct selection of MSC is mandatory, based on their functional potential, as well as the need to integrate all the existing information to achieve an optimal improvement of MSC features in the artificial niche. Keywords Regenerative medicine • Aging diseases • Diabetes • Lupus • Secretome • Conditioned medium • Extracellular vesicles • Exosomes Abbreviations 2D Two-dimensional 3D Three-dimensional AD Adipose-derived AD-MSC Adipose-derived mesenchymal stem cell Ad-FKN Adenoviral vector fractalkine gene BM Bone marrow BM-MSC Bone marrow-derived mesenchymal stem cell bBM-MSC Bovine bone marrow-derived mesenchymal stem cell BNDF Brain-derived neurotrophic factor CD Cluster of differentiation cGMP Current good manufacturing practice Cellular and Molecular Life Sciences Luis A. Costa and Noemi Eiro contributed equally to this work.

Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, anti-oxidative, or angiogenic activity. In addition, recent studies also demonstrate that depletion and/or dysfunction of MSCs are associated with several systemic diseases, such as lupus, diabetes, psoriasis, and rheumatoid arthritis, as well as with aging and frailty syndrome. In this review, we hypothesize about the role of MSCs as keepers of tissue homeostasis as well as modulators in a variety of inflammatory and degenerative systemic diseases. This scenario opens the possibility for the use of secretome-derived products from MSCs as new therapeutic agents in order to restore tissue homeostasis, instead of the classical paradigm “one disease, one drug”.

Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.

Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.

Mesenchymal (stem) stromal cells (MSC) can be a therapeutic alternative for COVID-19 considering their anti-inflammatory, regenerative, angiogenic, and even antimicrobial capacity. Preliminary data point to therapeutic interest of MSC for patients with COVID-19, and their effect seems based on the MSC's ability to curb the cytokine storm caused by COVID-19. In fact, promising clinical studies using MSC to treat COVID-19, are currently underway. For this reason, now is the time to firmly consider new approaches to MSC research that addresses key issues, like selecting the most optimal type of MSC for each indication, assuming the heterogeneity of the donor-dependent MSC and the biological niche where MSC are located.

Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a “galaxy” of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of “Exogenous Restitution of Intercellular Signalling of Stem Cells” (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.

The teeth, made up of hard and soft tissues, represent complex functioning structures of the oral cavity, which are frequently affected by processes that cause structural damage that can lead to their loss. Currently, replacement therapy such as endodontics or implants, restore structural defects but do not perform any biological function, such as restoring blood and nerve supplies. In the search for alternatives to regenerate the dental pulp, two alternative regenerative endodontic procedures (REP) have been proposed: (I) cell-free REP (based in revascularization and homing induction to remaining dental pulp stem cells (DPSC) and even stem cells from apical papilla (SCAP) and (II) cell-based REP (with exogenous cell transplantation). Regarding the last topic, we show several limitations with these procedures and therefore, we propose a novel regenerative approach in order to revitalize the pulp and thus restore homeostatic functions to the dentin-pulp complex. Due to their multifactorial biological effects, the use of mesenchymal stem cells (MSC)-derived secretome from non-dental sources could be considered as inducers of DPSC and SCAP to completely regenerate the dental pulp. In partial pulp damage, appropriate stimulate DPSC by MSC-derived secretome could contribute to formation and also to restore the vasculature and nerves of the dental pulp.

No abstract