Journal Article•
Therapeutic potential of human adipose-derived stem cell exosomes in stress urinary incontinence – an in vitro and in vivo study
TL;DR: In this article, the authors evaluated whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model.
Abstract: Background/Aims: To evaluate whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model. Methods: For the in vitro study, a Cell Counting Kit-8 (CCK-8) array and proteomic analysis were performed. For the in vivo study, female rats were divided into four groups: sham, SUI, adipose-derived stem cell (ADSC), and exosomes (n = 12 each). The SUI model was generated by pudendal nerve transection and vaginal dilation. Vehicle, hADSCs, or exosomes were injected into the peripheral urethra. After 2, 4, and 8 weeks, the rats underwent cystometrography and leak point pressure (LPP) testing, and tissues were harvested for histochemical analyses. Results: The CCK-8 experiment demonstrated that ADSC-derived exosomes could enhance the growth of skeletal muscle and Schwann cell lines in a dose-dependent manner. Proteomic analysis revealed that ADSC-derived exosomes contained various proteins of different signaling pathways. Some of these proteins are associated with the PI3K-Akt, Jak-STAT, and Wnt pathways, which are related to skeletal muscle and nerve regeneration and proliferation. In vivo experiments illustrated that rats of the exosome group had higher bladder capacity and LPP, and had more striated muscle fibers and peripheral nerve fibers in the urethra than rats of the SUI group. Both urethral function and histology of rats in the exosome group were slightly better than those in the ADSC group. Conclusions: Local injection of hADSC-derived exosomes improved functional and histological recovery after SUI.
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TL;DR: The characteristics of exosomes derived from ADSCs (ADSC-Exos), their functions in different biological processes, the latest research achievements, their limitations in cell-free therapy, and further insights into their clinical application potential for the treatment of certain diseases are introduced.
Abstract: Exosomes are extracellular membranous nanovesicles that mediate local and systemic intercellular communication by transporting proteins or nucleic acids (DNA and RNA) into target cells, thus altering the behaviors of recipient cells. Recent studies have revealed that these vesicles play a critical role in many biological functions, such as cell proliferation, immune regulation, nerve regeneration, and cancer. Adipose-derived stem cells (ADSCs) are now considered a multipotent and abundant tool in the field of cell therapy and regenerative medicine. ADSCs can produce and secrete many exosomes, which inherit multiple functions of cells. Therefore, in this review, we will introduce the characteristics of exosomes derived from ADSCs (ADSC-Exos), describe their functions in different biological processes, summarize the latest research achievements, describe their limitations in cell-free therapy, and provide further insights into their clinical application potential for the treatment of certain diseases.
142 citations
TL;DR: A synthetic summary of research conducted in vitro and in vivo by employing animal models and within initial clinical trials focusing on neurological, cardiovascular, liver, kidney, and skin diseases provides encouraging evidence about MSC-EVs pro-regenerative capacity in various models of diseases.
Abstract: Mesenchymal stem/ stromal cells (MSCs) represent progenitor cells of various origin with multiple differentiation potential, representing the most studied population of stem cells in both in vivo pre-clinical and clinical studies. MSCs may be found in many tissue sources including extensively studied adipose tissue (ADSCs) and umbilical cord Wharton’s jelly (UC-MSCs). Most of sanative effects of MSCs are due to their paracrine activity, which includes also release of extracellular vesicles (EVs). EVs are small, round cellular derivatives carrying lipids, proteins, and nucleic acids including various classes of RNAs. Due to several advantages of EVs when compare to their parental cells, MSC-derived EVs are currently drawing attention of several laboratories as potential new tools in tissue repair. This review focuses on pro-regenerative properties of EVs derived from ADSCs and UC-MSCs. We provide a synthetic summary of research conducted in vitro and in vivo by employing animal models and within initial clinical trials focusing on neurological, cardiovascular, liver, kidney, and skin diseases. The summarized studies provide encouraging evidence about MSC-EVs pro-regenerative capacity in various models of diseases, mediated by several mechanisms. Although, direct molecular mechanisms of MSC-EV action are still under investigation, the current growing data strongly indicates their potential future usefulness for tissue repair.
40 citations
TL;DR: This review focuses on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation in human stem cells.
Abstract: Stem cells are undifferentiated cells that can give rise to several different cell types and can self-renew. Given their ability to differentiate into different lineages, stem cells retain huge therapeutic potential for regenerative medicine. Therefore, the understanding of the signaling pathways involved in stem cell pluripotency maintenance and differentiation has a paramount importance in order to understand these biological processes and to develop therapeutic strategies. In this review, we focus on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation. Precisely, in human stem cells, the PI3K cascade is involved in different processes from pluripotency and induced pluripotent stem cell (iPSC) reprogramming to mesenchymal and oral mesenchymal differentiation, through different and interconnected mechanisms.
26 citations
TL;DR: ADSC EVs were found to exert effects on angiogenesis, cell survival and apoptosis, inflammation, tissue regeneration, and reduction of disease pathology.
Abstract: Summary Introduction Extracellular vesicles (EVs) are cell-secreted packages that deliver cargo to target cells to effect functional and phenotypic changes. They are secreted by many different cell types, including adipose-derived stem cells (ADSCs), which are a promising field of study in regenerative medicine. Our aim was to perform a systematic review of the literature to summarize the scientific work that has been conducted on ADSC EVs to date. Methods The Pubmed database was queried with keywords (and variations of) “adipose derived stem cell,” “stromal vascular fraction,” and “extracellular vesicles.” We excluded review papers, then manually screened articles based on title and abstract. Full-text articles were assessed for eligibility to include in final review. Results While an extensive body of research exists on EVs, a much smaller proportion of that is original research on ADSC EVs. Of 44 manuscripts that met our database search criteria, 21 articles were selected for our systematic review. Conclusion ADSC EVs were found to exert effects on angiogenesis, cell survival and apoptosis, inflammation, tissue regeneration, and reduction of disease pathology. Further studies examine characteristics of ADSC EVs. Future work should aim to further detail the safety profiles of ADSC EVs given their potential for cell-based therapies. The body of research studies characterizing ADSC EVs continues to expand, and much work remains to be done before human pilot studies can be considered. To our knowledge, we offer the first systematic review summarizing the research on ADSC EVs and their determined roles to date.
26 citations
TL;DR: Recent advances in knowledge of the role of exosome in GDM and related areas are reviewed and the possibilities for translating exosomes as therapeutic agents in the GDM clinical setting are discussed.
Abstract: Gestational diabetes Mellitus (GDM) is a complex clinical condition that promotes pelvic floor myopathy, thus predisposing sufferers to urinary incontinence (UI). GDM usually regresses after birth. Nonetheless, a GDM history is associated with higher risk of subsequently developing type 2 diabetes, cardiovascular diseases (CVD) and UI. Some aspects of the pathophysiology of GDM remain unclear and the associated pathologies (outcomes) are poorly addressed, simultaneously raising public health costs and diminishing women's quality of life. Exosomes are small extracellular vesicles produced and actively secreted by cells as part of their intercellular communication system. Exosomes are heterogenous in their cargo and depending on the cell sources and environment, they can mediate both pathogenetic and therapeutic functions. With the advancement in knowledge of exosomes, new perspectives have emerged to support the mechanistic understanding, prediction/diagnosis and ultimately, treatment of the post-GMD outcomes. Here, we will review recent advances in knowledge of the role of exosomes in GDM and related areas and discuss the possibilities for translating exosomes as therapeutic agents in the GDM clinical setting.
24 citations
References
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TL;DR: Next to existing terminology of the lower urinary tract, due to its increasing complexity, the terminology for pelvic floor dysfunction in women may be better updated by a female‐specific approach and clinically based consensus report.
Abstract: Introduction and hypothesis Next to existing terminology of the lower urinary tract, due to its increasing complexity, the terminology for pelvic floor dysfunction in women may be better updated by a female-specific approach and clinically based consensus report. Methods This report combines the input of members of the Standardization and Terminology Committees of two Inter
2,500 citations
TL;DR: The laminins are a family of glycoproteins that provide an integral part of the structural scaffolding of basement membranes in almost every animal tissue and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors.
Abstract: The laminins are a family of glycoproteins that provide an integral part of the structural scaffolding of basement membranes in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta, and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins can self-assemble, bind to other matrix macromolecules, and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors. Through these interactions, laminins critically contribute to cell differentiation, cell shape and movement, maintenance of tissue phenotypes, and promotion of tissue survival. Recent advances in the characterization of genetic disruptions in humans, mice, nematodes and flies have revealed developmental roles for the different laminin subunits in diverse cell types, affecting differentiation from blastocyst formation to the post-natal period. These genetic defects have challenged some of the previous concepts about basement membranes and have shed new light on the diversity and complexity of laminin functions as well as established the molecular basis of several human diseases.
1,242 citations
TL;DR: In contrast, the vast majority of small-sized clinical trials conducted with mesenchymal stem/stromal cells in regenerative medicine applications has not reported major health concerns, suggesting that MSC therapies could be relatively safe.
Abstract: Stem cell therapy holds the promise to treat degenerative diseases, cancer and repair of damaged tissues for which there are currently no or limited therapeutic options. The potential of stem cell therapies has long been recognised and the creation of induced pluripotent stem cells (iPSC) has boosted the stem cell field leading to increasing development and scientific knowledge. Despite the clinical potential of stem cell based medicinal products there are also potential and unanticipated risks. These risks deserve a thorough discussion within the perspective of current scientific knowledge and experience. Evaluation of potential risks should be a prerequisite step before clinical use of stem cell based medicinal products. The risk profile of stem cell based medicinal products depends on many risk factors, which include the type of stem cells, their differentiation status and proliferation capacity, the route of administration, the intended location, in vitro culture and/or other manipulation steps, irreversibility of treatment, need/possibility for concurrent tissue regeneration in case of irreversible tissue loss, and long-term survival of engrafted cells. Together these factors determine the risk profile associated with a stem cell based medicinal product. The identified risks (i.e. risks identified in clinical experience) or potential/theoretical risks (i.e. risks observed in animal studies) include tumour formation, unwanted immune responses and the transmission of adventitious agents. Currently, there is no clinical experience with pluripotent stem cells (i.e. embryonal stem cells and iPSC). Based on their characteristics of unlimited self-renewal and high proliferation rate the risks associated with a product containing these cells (e.g. risk on tumour formation) are considered high, if not perceived to be unacceptable. In contrast, the vast majority of small-sized clinical trials conducted with mesenchymal stem/stromal cells (MSC) in regenerative medicine applications has not reported major health concerns, suggesting that MSC therapies could be relatively safe. However, in some clinical trials serious adverse events have been reported, which emphasizes the need for additional knowledge, particularly with regard to biological mechanisms and long term safety.
571 citations
TL;DR: Improved neurological impairment and long‐term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow‐derived MSC lineages, providing clinically relevant evidence warranting rapid proof‐of‐concept studies in stroke patients.
Abstract: Althoughtheinitialconceptsofstemcelltherapyaimedatreplacinglosttissue,morerecentevidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain’s capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects.In order to define whether EVs indeedimprove postischemic neurologicalimpairmentandbrainremodeling,wesystematicallycomparedtheeffectsofmesenchymalstem cell(MSC)-derivedEVs(MSC-EVs)withMSCsthatwerei.v.deliveredtomiceondays1,3,and5(MSCEVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral bloodandbrain,andcerebralangiogenesisandneurogenesiswereanalyzed.Improvedneurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1–13
555 citations
TL;DR: The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review.
427 citations