Adipose-Derived Stem Cells (ADSCs) and Growth Differentiation Factor 11 (GDF11): Regenerative and Antiaging Capacity for the Skin

Adipose-derived stem cells (ADSCs) have proven their efficiency in wound healing and skin regeneration in vitro and in vivo. They were reported to differentiate into skin cell types and migrate to wounded sites to restore cell deficiencies and functions. Secretome of ADSCs is involved in the migration and proliferation of dermal fibroblasts (DFs) and keratinocytes where growth differentiation factor 11 (GDF11) and transforming growth factor-β (TGF-β) are expected to play the principal role. Both factors are implicated in immune responses, skin cell differentiation, proliferation and pigmentation, migration and secretion of the extracellular matrix proteins. Increasing evidence has pointed the fact that ADSCs are expected to cross-react with GDF11 to ensure DF and keratinocytes proliferation to reverse the aging process. Moreover, these factors share similar intracellular mechanisms pathways that are SMAD-dependent, and target different cellular mechanisms related to regeneration or rejuvenation. This intriguing balance between GDF11-dependent aging and TGF-β-dependent regeneration still remains unclear and might be regulated in a spatio-temporal manner. Considering the clinical relevance of the mechanisms slowing or delaying the onset of age, we aimed to clarify the involvement of cell signaling pathways related to GDF11 and TGF-β in balancing cell rejuvenation and cell regeneration. Increasing the organ lifespan and functionality might be challenging issues

Exosomes and Micro-RNAs in Aging Process

Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). Exosomes’ cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals. However, their underlying mechanisms modulating cell senescence and aging are still not fully understood, and little was reported on the involvement of mi-RNAs in cell or tissue longevity. In this review, we summarize exosome biogenesis and mi-RNA synthesis and loading mechanism into exosomes’ cargo. Additionally, we highlight the molecular mechanisms of exosomes and exosome-derived mi-RNA regulation in the different aging processes

Regenerative Capacity of Adipose Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs)

Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases

Skin Immunomodulation during Regeneration: Emerging New Targets

Adipose-Derived Stem Cells (ADSC) are present within the hypodermis and are also expected to play a pivotal role in wound healing, immunomodulation, and rejuvenation activities. They orchestrate, through their exosome, the mechanisms associated to cell differentiation, proliferation, and cell migration by upregulating genes implicated in different functions including skin barrier, immunomodulation, cell proliferation, and epidermal regeneration. ADSCs directly interact with their microenvironment and specifically the immune cells, including macrophages and T and B cells, resulting in differential inflammatory and anti-inflammatory mechanisms impacting, in return, ADSCs microenvironment and thus skin function. These useful features of ADSCs are involved in tissue repair, where the required cell proliferation, angiogenesis, and anti-inflammatory responses should occur rapidly in damaged sites. Different pathways involved have been reported such as Growth Differentiation Factor-11 (GDF11), Tumor Growth Factor (TGF)-β, Metalloproteinase (MMP), microRNA, and inflammatory cytokines that might serve as specific biomarkers of their immunomodulating capacity. In this review, we try to highlight ADSCs’ network and explore the potential indicators of their immunomodulatory effect in skin regeneration and aging. Assessment of these biomarkers might be useful and should be considered when designing new clinical therapies using ADSCs or their specific exosomes focusing on their immunomodulation activity

Skin Immunomodulation during Regeneration: Emerging New Targets

Adipose-Derived Stem Cells (ADSC) are present within the hypodermis and are also expected to play a pivotal role in wound healing, immunomodulation, and rejuvenation activities. They orchestrate, through their exosome, the mechanisms associated to cell differentiation, proliferation, and cell migration by upregulating genes implicated in different functions including skin barrier, immunomodulation, cell proliferation, and epidermal regeneration. ADSCs directly interact with their microenvironment and specifically the immune cells, including macrophages and T and B cells, resulting in differential inflammatory and anti-inflammatory mechanisms impacting, in return, ADSCs microenvironment and thus skin function. These useful features of ADSCs are involved in tissue repair, where the required cell proliferation, angiogenesis, and anti-inflammatory responses should occur rapidly in damaged sites. Different pathways involved have been reported such as Growth Differentiation Factor-11 (GDF11), Tumor Growth Factor (TGF)-β, Metalloproteinase (MMP), microRNA, and inflammatory cytokines that might serve as specific biomarkers of their immunomodulating capacity. In this review, we try to highlight ADSCs’ network and explore the potential indicators of their immunomodulatory effect in skin regeneration and aging. Assessment of these biomarkers might be useful and should be considered when designing new clinical therapies using ADSCs or their specific exosomes focusing on their immunomodulation activity

Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases

This study was funded by the Spanish ISCIII Health Research Fund and the European Regional Development Fund (FEDER) through research grants PI12/01097, PI15/02015, PI18/00337 (F.M.), PIE16-00045 (J.A.M.), DTS19/00145 (J.A.M.) and PI18/00330 (K.B.). The study was also supported by the Ministry of Science, Innovation and Universities (MICIU, RTI2018-101309-B-C22, FEDER funds), by the Consejeria de Economia, Conocimiento, Empresas y Universidad de la Junta de Andalucia (SOMM17/6109/UGR, FEDER Funds), the Chair of "Doctors Galera-Requena in cancer stem cell research" (CMC-CTS963) and the Junta de Andalucia Health and Families Department (CARTPI-0001-201). The CECEyU and CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) provided the following research grants: 2016000073391-TRA, 2016000073332-TRA, PI57069 and PAIDI-Bio326 (F.M.) and PI-0014-2016 (K.B.). K.B. was also on a Nicolas Monardes Regional Ministry of Health contract (0006/2018). H.A. held a Research Excellence PhD Fellowship (2UAE2020) from the National Center for Scientific and Technical Research (CNRST). L.M. was supported by the Mohammed VI Polytechnic University of Morocco.Data Availability Statement: The data presented in this study are available on request from the corresponding authors.Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application. Simple Summary: The aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents.Spanish ISCIII Health Research FundEuropean Union (EU) PI12/01097 PI15/02015 PI18/00337 PIE16-00045 DTS19/00145 PI18/00330Ministry of Science, Innovation and Universities (MICIU) RTI2018-101309-B-C22Junta de Andalucia SOMM17/6109/UGRChair of "Doctors Galera-Requena in cancer stem cell research" CMC-CTS963Junta de Andalucia CARTPI-0001-201CECEyU of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) 2016000073391-TRA 2016000073332-TRA PI57069 PAIDI-Bio326 PI-0014-2016CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) 2016000073391-TRA 2016000073332-TRA PI57069 PAIDI-Bio326 PI-0014-2016Nicolas Monardes Regional Ministry of Health 0006/2018National Center for Scientific and Technical Research (CNRST) 2UAE2020Mohammed VI Polytechnic University of Morocc

Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing

Adipose tissue derived stem cells (ADSCs) are mesenchymal stem cells identified within subcutaneous tissue at the base of the hair follicle (dermal papilla cells), in the dermal sheets (dermal sheet cells), in interfollicular dermis, and in the hypodermis tissue. These cells are expected to play a major role in regulating skin regeneration and aging-associated morphologic disgraces and structural deficits. ADSCs are known to proliferate and differentiate into skin cells to repair damaged or dead cells, but also act by an autocrine and paracrine pathway to activate cell regeneration and the healing process. During wound healing, ADSCs have a great ability in migration to be recruited rapidly into wounded sites added to their differentiation towards dermal fibroblasts (DF), endothelial cells, and keratinocytes. Additionally, ADSCs and DFs are the major sources of the extracellular matrix (ECM) proteins involved in maintaining skin structure and function. Their interactions with skin cells are involved in regulating skin homeostasis and during healing. The evidence suggests that their secretomes ensure: (i) The change in macrophages inflammatory phenotype implicated in the inflammatory phase, (ii) the formation of new blood vessels, thus promoting angiogenesis by increasing endothelial cell differentiation and cell migration, and (iii) the formation of granulation tissues, skin cells, and ECM production, whereby proliferation and remodeling phases occur. These characteristics would be beneficial to therapeutic strategies in wound healing and skin aging and have driven more insights in many clinical investigations. Additionally, it was recently presented as the tool key in the new free-cell therapy in regenerative medicine. Nevertheless, ADSCs fulfill the general accepted criteria for cell-based therapies, but still need further investigations into their efficiency, taking into consideration the host-environment and patient-associated factors

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress, and Inflammation in Protective and Adaptive Responses

International audienceThe potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties

Anti-Aging Effects of GDF11 on Skin

International audienceHuman skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases