Advances in mesenchymal stem cell conditioned medium-mediated periodontal tissue regeneration.
Lin Hongbing,Chen Huishan,Zhao Xuetao,Chen Zhen,Zhang Peipei,Tian Yue,Wang Yawei,Ding Tong,Wang Lijing,Shen Yuqin
Journal of translational medicine
Periodontitis is a chronic inflammatory disease that leads to the destruction of both soft and hard periodontal tissues. Complete periodontal regeneration in clinics using the currently available treatment approaches is still a challenge. Mesenchymal stem cells (MSCs) have shown promising potential to regenerate periodontal tissue in various preclinical and clinical studies. The poor survival rate of MSCs during in vivo transplantation and host immunogenic reaction towards MSCs are the main drawbacks of direct use of MSCs in periodontal tissue regeneration. Autologous MSCs have limited sources and possess patient morbidity during harvesting. Direct use of allogenic MSCs could induce host immune reaction. Therefore, the MSC-based indirect treatment approach could be beneficial for periodontal regeneration in clinics. MSC culture conditioned medium (CM) contains secretomes that had shown immunomodulatory and tissue regenerative potential in pre-clinical and clinical studies. MSC-CM contains a cocktail of growth factors, cytokines, chemokines, enzymes, and exosomes, extracellular vesicles, etc. MSC-CM-based indirect treatment has the potential to eliminate the drawbacks of direct use of MSCs for periodontal tissue regeneration. MSC-CM holds the tremendous potential of bench-to-bed translation in periodontal regeneration applications. This review focuses on the accumulating evidence indicating the therapeutic potential of the MSC-CM in periodontal regeneration-related pre-clinical and clinical studies. Recent advances on MSC-CM-based periodontal regeneration, existing challenges, and prospects are well summarized as guidance to improve the effectiveness of MSC-CM on periodontal regeneration in clinics.
10.1186/s12967-021-03125-5
Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage.
Hong Liming,Yan Long,Xin Zhimin,Hao Jie,Liu Wenjing,Wang Shuyu,Liao Shujie,Wang Hongmei,Yang Xiaokui
Journal of molecular cell biology
Chemotherapeutic agents are extensively used to treat malignancies. However, chemotherapy-induced ovarian damage and reduced fertility are severe side effects. Recently, stem cell transplantation has been reported to be an effective strategy for premature ovarian insufficiency (POI) treatment, but safety can still be an issue in stem cell-based therapy. Here, we show the protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) on a cisplatin (Cs)-induced ovarian injury model. hUCMSC-CM can relieve Cs-induced depletion of follicles and preserve fertility. In addition, hUCMSC-CM can decrease apoptosis of oocytes and granulosa cells induced by Cs. RNA sequencing analysis reveals the differentially expressed genes of ovaries after Cs and hUCMSC-CM treatments, including genes involved in cell apoptosis. Furthermore, we show that the granulocyte colony-stimulating factor (G-CSF)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway plays an important role in protecting granulosa cells from Cs-induced apoptosis. Together, we confirm the protective effects of hUCMSC-CM on ovarian reserve and fertility in mice treated with Cs, highlighting the remarkable therapeutic effects of hUCMSC-CM.
10.1093/jmcb/mjz105
Cell-free derivatives from mesenchymal stem cells are effective in wound therapy.
Mishra Pravin J,Mishra Prasun J,Banerjee Debabrata
World journal of stem cells
AIM:To compare the efficacy of cell-free derivatives from Bone marrow derived human mesenchymal stem cells (hMSCs) in wound therapy. METHODS:hMSCs have been shown to play an important role in wound therapy. The present study sought to compare efficacy of hMSCs and cell-free derivatives of hMSCs, which may be clinically more relevant as they are easier to prepare, formulate and transport. hMSCs were isolated from human bone marrow and cultured. Multi lineage differentiation of hMSCs was performed to confirm their identity. The ability of hMSCs to migrate was evaluated using in vitro and in vivo migration assays. Cell lysates and conditioned medium concentrate was prepared from hMSCs (see Methods for details). Wounds were induced in mice and wound areas were measure before and after cell and cell-free derivative treatment. RNA and proteins were extracted from the skin and cytokine levels were measured. RESULTS:Co-culture of hMSCs with keratinocytes resulted in increased expression of CXCL-12 (SDF1) and ENA78 (CXCL-5) in the conditioned media indicating that the hMSCs can respond to signals from keratinocytes. Accelerated wound closure was observed when hMSCs were injected near the site of excisional wounds in athymic as well as NOD/SCID mice. Interestingly, cell-free lysates prepared from hMSCs were also effective in inducing accelerated wound closure and increased expression of SDF1 and CXCL-5 at the wound bed. Additionally, concentrated media from hMSCs as well as an emulsion containing lysates prepared from hMSCs was also found to be more effective in rapid re-epithelialization than fibroblasts or vehicle-alone control. Use of cell-free derivatives may help replace expensive wound care approaches including use of growth factors, epidermal/dermal substitutes, synthetic membranes, cytokines, and matrix components, and most importantly avoid transmission of pathogens from human and animal products. CONCLUSION:These results encourage development of derivatives of hMSCs for wound care and re-epithelialization applications.
10.4252/wjsc.v4.i5.35
Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics.
Stem cells international
Mesenchymal stem cells (MSCs) have attracted tremendous research interest due to their ability to repair tissues and reduce inflammation when implanted into a damaged or diseased site. These therapeutic effects have been largely attributed to the collection of biomolecules they secrete (i.e., their secretome). Recent studies have provided evidence that similar effects may be produced by utilizing only the secretome fraction containing extracellular vesicles (EVs). EVs are cell-derived, membrane-bound vesicles that contain various biomolecules. Due to their small size and relative mobility, they provide a stable mechanism to deliver biomolecules (i.e., biological signals) throughout an organism. The use of the MSC secretome, or its components, has advantages over the implantation of the MSCs themselves: (i) signals can be bioengineered and scaled to specific dosages, and (ii) the nonliving nature of the secretome enables it to be efficiently stored and transported. However, since the composition and therapeutic benefit of the secretome can be influenced by cell source, culture conditions, isolation methods, and storage conditions, there is a need for standardization of bioprocessing parameters. This review focuses on key parameters within the MSC culture environment that affect the nature and functionality of the secretome. This information is pertinent to the development of bioprocesses aimed at scaling up the production of secretome-derived products for their use as therapeutics.
10.1155/2018/9415367
Therapeutic applications of adipose cell-free derivatives: a review.
Cai Yuan,Li Jianyi,Jia Changsha,He Yunfan,Deng Chengliang
Stem cell research & therapy
BACKGROUND:Adipose-derived stem cells (ADSCs) have become one of the most utilized adult stem cells due to their abundance and accessibility. Recent studies have shown that paracrine cytokines, exosomes, and other active substances are the main factors through which ADSCs exert their biological effects. MAIN BODY:Adipose cell-free derivatives have been recently gaining attention as potential therapeutic agents for various human diseases. These derivatives include ADSC-conditioned medium (ADSC-CM), ADSC exosomes (ADSC-Exo), and cell-free adipose tissue extracts (ATEs), all of which can be conveniently carried, stored, and transported. Currently, research on ADSC-conditioned medium (ADSC-CM) and ADSC exosomes (ADSC-Exo) is surging. Moreover, cell-free adipose tissue extracts (ATEs), obtained by purely physical methods, have emerged as the focus of research in recent years. CONCLUSION:Adipose cell-free derivatives delivery can promote cell proliferation, migration, and angiogenesis, suppress cell apoptosis, and inflammation, as well as reduce oxidative stress and immune regulation. Thus, adipose cell-free derivatives have a broad therapeutic potential in many areas, as they possess anti-skin aging properties, promote wound healing, reduce scar formation, and provide myocardial protection and neuroprotection. This article summarizes these effects and reviews research progress in the use of adipose cell-free derivatives.
10.1186/s13287-020-01831-3
Synthetic bioreducible lipid-based nanoparticles for miRNA delivery to mesenchymal stem cells to induce neuronal differentiation.
Takeda Yuji S,Wang Ming,Deng Pu,Xu Qiaobing
Bioengineering & translational medicine
MicroRNA (miRNA) functions in tissue regeneration and determines the fate of stem cells. Nanoparticle-based miRNA delivery systems for therapeutic applications have been studied in clinical settings. However, gene delivery to stem cells is still a challenging issue. Lipid-like nanoparticles produced using combinatorial approaches have recently been used for delivery of a variety of biologics. In this study, we investigated the ability of these lipids to deliver miRNA to human mesenchymal stem cells (hMSCs). First, small library screening of bioreducible lipids was performed using fluorophore-conjugated miRNA to determine the optimal chemical structure for miRNA delivery to hMSCs. Next, miRNA-9 (miR-9), which promotes neuronal differentiation of stem cells, was delivered to hMSCs using the lipids identified from the library screening. Morphological changes of the cells and upregulation of neuronal marker genes were observed after the delivery of miR-9. The synthetic bioreducible lipids are effective in facilitating miRNA delivery to hMSCs and promoting the neuronal differentiation.
10.1002/btm2.10021
Acellular derivatives of mesenchymal stem cells prevent peritoneal adhesions in an animal model.
Rojo Daniel,Conget Paulette
The Journal of surgical research
BACKGROUND:Peritoneal adhesions are nonanatomical connections that bind organs to the abdominal wall or among them. They arise after peritoneal injury, which triggers an inflammatory response followed by a healing process that leads to fibrotic tissue formation. Mesenchymal stem cells and their secretion products, also referred to as acellular derivatives (ACDs), have anti-inflammatory, fibrinolytic, and antifibrogenic properties. The aim of this study was to determine the effect of intraoperative administration of ACD on the appearance, severity, and progression of peritoneal adhesions, in an animal model. MATERIALS AND METHODS:Cecal erosions were mechanically induced in adult mice. Before closure, the vehicle, ACD, or Seprafilm was administered. Seven days later, the presence and grade of peritoneal adhesions were assessed macroscopically. One, 3, and 7 d after intervention, molecular and cellular markers of inflammation, fibrinolysis, and fibrogenesis were evaluated both locally and systemically. RESULTS:ACDs avoided the appearance of clinically relevant peritoneal adhesions. The vehicle had no effect, and Seprafilm reduced them inconsistently. The antiadhesive effect of ACD was associated with an early reduction of proinflammatory cytokine (tumor necrosis factor-alpha and interferon-gamma) secretion and leukocyte (polymorphonuclears, mononuclears, and macrophages) infiltration. High levels of D-dimer, low fibrin deposits, low myofibroblasts infiltration, and less fibrosis were also observed. CONCLUSIONS:ACD administered at the end of abdominal surgeries prevents the formation of peritoneal adhesions due to the modulation of inflammatory, fibrinolytic, and fibrogenic processes.
10.1016/j.jss.2017.11.018
Effects of Mesenchymal Stem Cell Derivatives on Hematopoiesis and Hematopoietic Stem Cells.
Aqmasheh Sara,Shamsasanjan Karim,Akbarzadehlaleh Parvin,Pashoutan Sarvar Davod,Timari Hamze
Advanced pharmaceutical bulletin
Hematopoiesis is a balance among quiescence, self-renewal, proliferation, and differentiation, which is believed to be firmly adjusted through interactions between hematopoietic stem and progenitor cells (HSPCs) with the microenvironment. This microenvironment is derived from a common progenitor of mesenchymal origin and its signals should be capable of regulating the cellular memory of transcriptional situation and lead to an exchange of stem cell genes expression. Mesenchymal stem cells (MSCs) have self-renewal and differentiation capacity into tissues of mesodermal origin, and these cells can support hematopoiesis through release various molecules that play a crucial role in migration, homing, self-renewal, proliferation, and differentiation of HSPCs. Studies on the effects of MSCs on HSPC differentiation can develop modern solutions in the treatment of patients with hematologic disorders for more effective Bone Marrow (BM) transplantation in the near future. However, considerable challenges remain on realization of how paracrine mechanisms of MSCs act on the target tissues, and how to design a therapeutic regimen with various paracrine factors in order to achieve optimal results for tissue conservation and regeneration. The aim of this review is to characterize and consider the related aspects of the ability of MSCs secretome in protection of hematopoiesis.
10.15171/apb.2017.021
Nano-Ghosts: Biomimetic membranal vesicles, technology and characterization.
Oieni Jacopo,Levy Lior,Letko Khait Nitzan,Yosef Liat,Schoen Beth,Fliman Miguel,Shalom-Luxenburg Hagit,Malkah Dayan Natali,D'Atri Domenico,Cohen Anavy Noa,Machluf Marcelle
Methods (San Diego, Calif.)
Currently, nano-carriers for anti-cancer drug delivery are complex systems, which struggle with immunogenicity and enhanced permeability effect (EPR)-related problems that halt the clinical translation of many therapeutics. Consequently, a rapidly growing field of research has been focusing on biomimetic nano-vesicles (BNVs) as an effective delivery alternative. Nevertheless, the translation of many BNVs is limited due to scalability problems, inconsistent production process, and insufficient loading efficiency. Here we discuss the process of our previously published BNVs, termed Nano-Ghosts (NGs), which are produced from the membrane of mesenchymal stem cells. We demonstrate the flexibility of the process, while alternating physical methodologies (sonication or extrusion) to produce the NGs while preserving their desired characteristics. We also show that our NGs can be labeled using multiple methods (fluorescence, radiolabeling, and genetic engineering) for tracking and diagnostic purposes. Lastly, we demonstrate that the loading efficiency can be improved by using electroporation to accommodate a range of therapeutics (small molecules, peptides and DNA) that can be delivered by the NGs. Our results emphasize the robustness of the NGs technology, its versatility and a vast range of applications, differentiating it from other BNVs and leading the way towards clinical translation.
10.1016/j.ymeth.2019.11.013
Biomimetic recombinant of red blood cell membranes for improved photothermal therapy.
Wu Pengkai,Jiang Xing,Yin Shuai,Yang Ying,Liu Tianqing,Wang Kaikai
Journal of nanobiotechnology
BACKGROUND:RBC membrane derived nanoparticles (NPs) represent an emerging platform with prolonged circulation capacity for the delivery of active substances. For functionalize derived RBCs NPs, various strategies, such as biomimetic rebuilding of RBCs, chemical modification or inserting ligands, have been carried out to improve their performance. However, one potential adverse effect for these methods is the structural failure of membrane proteins, consequently affecting its original immune escape function. RESULTS:In this study, we reported a green technology of "disassembly-reassembly" to prepare biomimetic reconstituted RBCs membrane (rRBCs) by separating the endogenous proteins and lipids from nature RBC membrane. IR780 iodide was used as a pattern drug to verify the property and feasibility of rRBCs by constructing IR780@rRBC NPs with IR780@RBC NPs and free IR780 as controls. The results demonstrated the superiority of IR780@rRBC NPs in toxicity, stability, pharmacokinetics and pharmacodynamics compared with IR780@rRBC and free IR780. CONCLUSIONS:The reported "disassembly-reassembly" strategy shows great potential to produce controllable and versatile rRBC membrane-inspired delivery platform, which may be used to overcome the deficiency of functionalization in cell membrane coated nanoparticles .
10.1186/s12951-021-00949-7
Potential application of biomimetic exosomes in cardiovascular disease: focused on ischemic heart disease.
Kang In Sook,Kwon Kihwan
BMB reports
Cardiovascular disease, especially ischemic heart disease, is a major cause of mortality worldwide. Cardiac repair is one of the most promising strategies to address advanced cardiovascular diseases. Despite moderate improvement in heart function via stem cell therapy, there is no evidence of significant improvement in mortality and morbidity beyond standard therapy. The most salutary effect of stem cell therapy are attributed to the paracrine effects and the stem cell-derived exosomes are known as a major contributor. Hence, exosomes are emerging as a promising therapeutic agent and potent biomarkers of cardiovascular disease. Furthermore, they play a role as cellular cargo and facilitate intercellular communication. However, the clinical use of exosomes is hindered by the absence of a standard operating procedures for exosome isolation and characterization, problems related to yield, and heterogeneity. In addition, the successful clinical application of exosomes requires strategies to optimize cargo, improve targeted delivery, and reduce the elimination of exosomes. In this review, we discuss the basic concept of exosomes and stem cell-derived exosomes in cardiovascular disease, and introduce current efforts to overcome the limitations and maximize the benefit of exosomes including engineered biomimetic exosomes. [BMB Reports 2022; 55(1): 30-38].
Exosomes and miRNA-Loaded Biomimetic Nanovehicles, a Focus on Their Potentials Preventing Type-2 Diabetes Linked to Metabolic Syndrome.
Beuzelin Diane,Kaeffer Bertrand
Frontiers in immunology
Exosomes are small membrane vesicles of 30-150 nm, members of the extracellular vesicle family and secreted by various cell types. Different studies describe specific microRNA (miRNA) with altered expression in serum and/or plasma of patients suffering from diabetes or metabolic syndrome. Diabetic cardiomyocyte-derived exosomes loaded with miRNAs like miR-320-3p (or 320a) have been shown regulating angiogenesis on endothelial cell cultures. Insufficient myocardial angiogenesis is the major manifestation of diabetes-caused ischemic cardiovascular disease. Studies on transfer of functional microRNAs between mouse dendritic cells via exosomes have shown that some miRNAs (miR-320-3p, 29b-3p, 7a-5p) are distributed in immature and mature exosomes. Among these miRNAs, miR-320-3p is better known in epigenetics for silencing polr3d gene by binding to its promoter in Human Embryonic Kidney-293 cells. Moreover, quantitative and stoichiometric analysis of the microRNA content of exosomes highlights the lack of reliable natural source of such particles loaded with miRNA opening the need for tailoring exosomes or nanoparticles delivering efficiently miRNA intimately linked to immunity, metabolism and epigenetics in target cells. However, loading of extracellular mature miRNA into recipient cells comes with a cost by at least impeding dynamic localization of miRNAs in nucleoli or inefficient miRNA delivery due to rapid recycling by exonucleases. All these works are calling for the design of new biomimetic vehicles and assessment of miRNA functionality when delivered by natural or biomimetic nanoparticles in order to control metabolic diseases from infancy to adulthood.
10.3389/fimmu.2018.02711
Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics.
Theranostics
Exosomes are small extracellular vesicles with diameters of 30-150 nm. In both physiological and pathological conditions, nearly all types of cells can release exosomes, which play important roles in cell communication and epigenetic regulation by transporting crucial protein and genetic materials such as miRNA, mRNA, and DNA. Consequently, exosome-based disease diagnosis and therapeutic methods have been intensively investigated. However, as in any natural science field, the in-depth investigation of exosomes relies heavily on technological advances. Historically, the two main technical hindrances that have restricted the basic and applied researches of exosomes include, first, how to simplify the extraction and improve the yield of exosomes and, second, how to effectively distinguish exosomes from other extracellular vesicles, especially functional microvesicles. Over the past few decades, although a standardized exosome isolation method has still not become available, a number of techniques have been established through exploration of the biochemical and physicochemical features of exosomes. In this work, by comprehensively analyzing the progresses in exosome separation strategies, we provide a panoramic view of current exosome isolation techniques, providing perspectives toward the development of novel approaches for high-efficient exosome isolation from various types of biological matrices. In addition, from the perspective of exosome-based diagnosis and therapeutics, we emphasize the issue of quantitative exosome and microvesicle separation.
10.7150/thno.41580
Exosomes, a New Star for Targeted Delivery.
Chen Huizhi,Wang Liyan,Zeng Xinling,Schwarz Herbert,Nanda Himansu Sekhar,Peng Xinsheng,Zhou Yubin
Frontiers in cell and developmental biology
Exosomes are cell-secreted nanoparticles (generally with a size of 30-150 nm) bearing numerous biological molecules including nucleic acids, proteins and lipids, which are thought to play important roles in intercellular communication. As carriers, exosomes hold promise as advanced platforms for targeted drug/gene delivery, owing to their unique properties, such as innate stability, low immunogenicity and excellent tissue/cell penetration capacity. However, their practical applications can be limited due to insufficient targeting ability or low efficacy in some cases. In order to overcome these existing challenges, various approaches have been applied to engineer cell-derived exosomes for a higher selectivity and effectiveness. This review presents the state-of-the-art designs and applications of advanced exosome-based systems for targeted cargo delivery. By discussing experts' opinions, we hope this review will inspire the researchers in this field to develop more practical exosomal delivery systems for clinical applications.
10.3389/fcell.2021.751079
Extracellular vesicles in cardiovascular disease: Biological functions and therapeutic implications.
Pharmacology & therapeutics
Extracellular vesicles (EVs), including exosomes and microvesicles, are lipid bilayer particles naturally released from the cell. While exosomes are formed as intraluminal vesicles (ILVs) of the multivesicular endosomes (MVEs) and released to extracellular space upon MVE-plasma membrane fusion, microvesicles are generated through direct outward budding of the plasma membrane. Exosomes and microvesicles have same membrane orientation, different yet overlapping sizes; their cargo contents are selectively packed and dependent on the source cell type and functional state. Both exosomes and microvesicles can transfer bioactive RNAs, proteins, lipids, and metabolites from donor to recipient cells and influence the biological properties of the latter. Over the last decade, their potential roles as effective inter-tissue communicators in cardiovascular physiology and pathology have been increasingly appreciated. In addition, EVs are attractive sources of biomarkers for the diagnosis and prognosis of diseases, because they acquire their complex cargoes through cellular processes intimately linked to disease pathogenesis. Furthermore, EVs obtained from various stem/progenitor cell populations have been tested as cell-free therapy in various preclinical models of cardiovascular diseases and demonstrate unequivocally encouraging benefits. Here we summarize the findings from recent research on the biological functions of EVs in the ischemic heart disease and heart failure, and their potential as novel diagnostic biomarkers and therapeutic opportunities.
10.1016/j.pharmthera.2021.108025
The Potential of Stem Cells and Stem Cell-Derived Exosomes in Treating Cardiovascular Diseases.
Ni Jing,Sun Yuxi,Liu Zheng
Journal of cardiovascular translational research
In recent years, the cardiac protective mechanisms of stem cells have become a research focus. Increasing evidence has suggested that stem cells release vesicles, including exosomes and micro-vesicles. The content of these vesicles relies on an extracellular stimulus, and active ingredients are extensively being studied. Previous studies have confirmed that stem cell-derived exosomes have a cardiac protective function similar to that of stem cells, and promote angiogenesis, decrease apoptosis, and respond to stress. Compared to stem cells, exosomes are more stable without aneuploidy and immune rejection, and may be a promising and effective therapy for cardiovascular diseases. In this review, the biological functions and molecular mechanisms of stem cells and stem cell-derived exosomes are discussed.
10.1007/s12265-018-9799-8
Reassessment of Exosome Composition.
Cell
The heterogeneity of small extracellular vesicles and presence of non-vesicular extracellular matter have led to debate about contents and functional properties of exosomes. Here, we employ high-resolution density gradient fractionation and direct immunoaffinity capture to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material. Extracellular RNA, RNA-binding proteins, and other cellular proteins are differentially expressed in exosomes and non-vesicle compartments. Argonaute 1-4, glycolytic enzymes, and cytoskeletal proteins were not detected in exosomes. We identify annexin A1 as a specific marker for microvesicles that are shed directly from the plasma membrane. We further show that small extracellular vesicles are not vehicles of active DNA release. Instead, we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular-endosome-dependent but exosome-independent mechanism. This study demonstrates the need for a reassessment of exosome composition and offers a framework for a clearer understanding of extracellular vesicle heterogeneity.
10.1016/j.cell.2019.02.029
Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior.
Bobis-Wozowicz Sylwia,Kmiotek Katarzyna,Sekula Malgorzata,Kedracka-Krok Sylwia,Kamycka Elzbieta,Adamiak Marta,Jankowska Urszula,Madetko-Talowska Anna,Sarna Michal,Bik-Multanowski Miroslaw,Kolcz Jacek,Boruczkowski Dariusz,Madeja Zbigniew,Dawn Buddhadeb,Zuba-Surma Ewa K
Stem cells (Dayton, Ohio)
Microvesicles (MVs) are membrane-enclosed cytoplasmic fragments released by normal and activated cells that have been described as important mediators of cell-to-cell communication. Although the ability of human induced pluripotent stem cells (hiPSCs) to participate in tissue repair is being increasingly recognized, the use of hiPSC-derived MVs (hiPSC-MVs) in this regard remains unknown. Accordingly, we investigated the ability of hiPSC-MVs to transfer bioactive molecules including mRNA, microRNA (miRNA), and proteins to mature target cells such as cardiac mesenchymal stromal cells (cMSCs), and we next analyzed effects of hiPSC-MVs on fate and behavior of such target cells. The results show that hiPSC-MVs derived from integration-free hiPSCs cultured under serum-free and feeder-free conditions are rich in mRNA, miRNA, and proteins originated from parent cells; however, the levels of expression vary between donor cells and MVs. Importantly, we found that transfer of hiPSC components by hiPSC-MVs impacted on transcriptome and proteomic profiles of target cells as well as exerted proliferative and protective effects on cMSCs, and enhanced their cardiac and endothelial differentiation potential. hiPSC-MVs also transferred exogenous transcripts from genetically modified hiPSCs that opens new perspectives for future strategies to enhance MV content. We conclude that hiPSC-MVs are effective vehicles for transferring iPSC attributes to adult somatic cells, and hiPSC-MV-mediated horizontal transfer of RNAs and proteins to injured tissues may be used for therapeutic tissue repair. In this study, for the first time, we propose a new concept of use of hiPSCs as a source of safe acellular bioactive derivatives for tissue regeneration.
10.1002/stem.2078
Clinical applications of pluripotent stem cells and their derivatives: current status and future perspectives.
Regenerative medicine
Pluripotent stem cells (PSCs) can differentiate into specific cell types and thus hold great promise in regenerative medicine to treat certain diseases. Hence, several studies have been performed harnessing their salutary properties in regenerative medicine. Despite several challenges associated with the clinical applications of PSCs, worldwide efforts are harnessing their potential in the regeneration of damaged tissues. Several clinical trials have been performed using PSCs or their derivatives. However, the delay in publishing the data obtained in the trials has led to a lack of awareness about their outcomes, resulting in apprehension about cellular therapies. Here, the authors review the published papers containing data from recent clinical trials done with PSCs. PSC-derived extracellular vesicles hold great potential in regenerative therapy. Since published papers containing the data obtained in clinical trials on PSC-derived extracellular vesicles are not available yet, the authors have reviewed some of the pre-clinical work done with them.
10.2217/rme-2022-0045
Stem Cells and Their Derivatives-Implications for Alveolar Bone Regeneration: A Comprehensive Review.
Hollý Dušan,Klein Martin,Mazreku Merita,Zamborský Radoslav,Polák Štefan,Danišovič Ľuboš,Csöbönyeiová Mária
International journal of molecular sciences
Oral and craniofacial bone defects caused by congenital disease or trauma are widespread. In the case of severe alveolar bone defect, autologous bone grafting has been considered a "gold standard"; however, the procedure has several disadvantages, including limited supply, resorption, donor site morbidity, deformity, infection, and bone graft rejection. In the last few decades, bone tissue engineering combined with stem cell-based therapy may represent a possible alternative to current bone augmentation techniques. The number of studies investigating different cell-based bone tissue engineering methods to reconstruct alveolar bone damage is rapidly rising. As an interdisciplinary field, bone tissue engineering combines the use of osteogenic cells (stem cells/progenitor cells), bioactive molecules, and biocompatible scaffolds, whereas stem cells play a pivotal role. Therefore, our work highlights the osteogenic potential of various dental tissue-derived stem cells and induced pluripotent stem cells (iPSCs), the progress in differentiation techniques of iPSCs into osteoprogenitor cells, and the efforts that have been made to fabricate the most suitable and biocompatible scaffold material with osteoinductive properties for successful bone graft generation. Moreover, we discuss the application of stem cell-derived exosomes as a compelling new form of "stem-cell free" therapy.
10.3390/ijms222111746
Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype.
Frank Ann-Christin,Ebersberger Stefanie,Fink Annika F,Lampe Sebastian,Weigert Andreas,Schmid Tobias,Ebersberger Ingo,Syed Shahzad Nawaz,Brüne Bernhard
Nature communications
Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment.
10.1038/s41467-019-08989-2
Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment.
Cell death and differentiation
Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8 T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2-DNMT1-IFN-γ signalling to suppress and exhaust CD8 T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.
10.1038/s41418-020-00618-6