scholarly journals Perspectives for Future Use of Extracellular Vesicles from Umbilical Cord- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells in Regenerative Therapies—Synthetic Review

2020 ◽  
Vol 21 (3) ◽  
pp. 799 ◽  
Author(s):  
Joanna Lelek ◽  
Ewa K. Zuba-Surma
Keyword(s):  
Adipose Tissue ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Differentiation Potential

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.

scholarly journals Delivery of miR-424-5p via Extracellular Vesicles Promotes the Apoptosis of MDA-MB-231 TNBC Cells in the Tumor Microenvironment

2021 ◽  
Vol 22 (2) ◽  
pp. 844
Author(s):  
Yueyuan Zhou ◽  
Yusuke Yamamoto ◽  
Fumitaka Takeshita ◽  
Tomofumi Yamamoto ◽  
Zhongdang Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Adipose Tissue ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Triple Negative ◽  
Intratumoral Administration ◽  
Immunosuppressive Microenvironment

Programmed cell death ligand-1 (PD-L1) overexpressed on cancer cells has emerged as a key inhibitor that maintains the immunosuppressive microenvironment through its interaction with the PD-1 receptor in cancer. Here, we demonstrated that miR-424-5p delivery via extracellular vesicles (EVs) derived from adipose tissue-mesenchymal stromal cells (AT-MSCs) partly promotes proinflammation and enhances antitumor cytotoxicity in vitro and in vivo. Triple negative breast cancer (TNBC) exhibits increased expression of PD-L1, and PD-L1 is positively correlated with the overall survival of patients with TNBC. PD-L1 shows relatively higher expression in MDA-MB-231 (MM231) cells and can be downregulated by miR-424-5p. Furthermore, miR-424-5p transported by EVs can increase the secretion of proinflammatory cytokines, decrease the secretion of anti-inflammatory cytokines and promote the apoptosis of tumor cells. The intratumoral administration of miR-424-5p-EVs significantly slowed tumor growth. In conclusion, these results demonstrate that EVs may serve as a delivery system for novel immunotherapies for TNBC through the miR-424-5p/PD-L1 pathway.

scholarly journals Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications

2022 ◽  
Vol 2022 ◽  
pp. 1-23
Author(s):  
E. Russo ◽  
M. Caprnda ◽  
P. Kruzliak ◽  
P. G. Conaldi ◽  
C. V. Borlongan ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Stromal Cells ◽  
Cartilage Regeneration ◽  
Multilineage Differentiation ◽  
Differentiation Potential ◽  
Cartilage Diseases ◽  
Abundant Supply ◽  
Adult Mscs

Chondropathies are increasing worldwide, but effective treatments are currently lacking. Mesenchymal stromal cell (MSCs) transplantation represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA) and rheumatoid arthritis (RA). Umbilical cord- (UC-) MSCs gained increasing interest due to their multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties as well as higher proliferation rates, abundant supply along with no risks for the donor compared to adult MSCs. In addition, UC-MSCs are physiologically adapted to survive in an ischemic and nutrient-poor environment as well as to produce an extracellular matrix (ECM) similar to that of the cartilage. All these characteristics make UC-MSCs a pivotal source for a stem cell-based treatment of chondropathies. In this review, the regenerative potential of UC-MSCs for the treatment of cartilage diseases will be discussed focusing on in vitro, in vivo, and clinical studies.

scholarly journals Developmental aspects of adipose tissue in GH receptor and prolactin receptor gene disrupted mice: site-specific effects upon proliferation, differentiation and hormone sensitivity

2006 ◽  
Vol 191 (1) ◽  
pp. 101-111 ◽  
Author(s):  
David J Flint ◽  
Nadine Binart ◽  
Stephanie Boumard ◽  
John J Kopchick ◽  
Paul Kelly
Keyword(s):  
Adipose Tissue ◽  
Receptor Gene ◽  
Metabolic Effects ◽  
Wild Type ◽  
Extrinsic Factors ◽  
Differentiation Potential ◽  
Site Specific ◽  
Proliferation And Differentiation

Direct metabolic effects of GH on adipose tissue are well established, but effects of prolactin (PRL) have been more controversial. Recent studies have demonstrated PRL receptors on adipocytes and effects of PRL on adipose tissue in vitro. The role of GH in adipocyte proliferation and differentiation is also controversial, since GH stimulates adipocyte differentiation in cell lines, whereas it stimulates proliferation but inhibits differentiation of adipocytes in primary cell culture. Using female gene disrupted (ko) mice, we showed that absence of PRL receptors (PRLRko) impaired development of both internal and s.c. adipose tissue, due to reduced numbers of adipocytes, an effect differing from that of reduced food intake, where cell volume is decreased. In contrast, GHRko mice exhibited major decreases in the number of internal adipocytes, whereas s.c. adipocyte numbers were increased, even though body weight was decreased by 40–50%. The changes in adipose tissue in PRLRko mice appeared to be entirely due to extrinsic factors since preadipocytes proliferated and differentiated in similar fashion to wild-type animals in vitro and their response to insulin and isoproterenol was similar to wild-type animals. This contrasted with GHRko mice, where s.c. adipocytes proliferated, differentiated, and responded to hormones in identical fashion to controls, whereas parametrial adipocytes exhibited markedly depressed proliferation and differentiation potential and failed to respond to insulin or noradrenaline. Our results provide in vivo evidence that both GH and PRL stimulate differentiation of adipocytes but that the effects of GH are site specific and induce intrinsic changes in the precursor population, which are retained in vitro.

scholarly journals Umbilical cord as a long-term source of activatable mesenchymal stromal cells for immunomodulation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anton Selich ◽  
Katharina Zimmermann ◽  
Michel Tenspolde ◽  
Oliver Dittrich-Breiholz ◽  
Constantin von Kaisenberg ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Induction Time ◽  
Dna Barcode ◽  
Human Umbilical Cord ◽  
Time Points

Abstract Background Mesenchymal stromal cells (MSCs) are used in over 800 clinical trials mainly due to their immune inhibitory activity. Umbilical cord (UC), the second leading source of clinically used MSCs, is usually cut in small tissue pieces. Subsequent cultivation leads to a continuous outgrowth of MSC explant monolayers (MSC-EMs) for months. Currently, the first MSC-EM culture takes approximately 2 weeks to grow out, which is then expanded and applied to patients. The initiating tissue pieces are then discarded. However, when UC pieces are transferred to new culture dishes, MSC-EMs continue to grow out. In case the functional integrity of these cells is maintained, later induced cultures could also be expanded and used for cell therapy. This would drastically increase the number of available cells for each patient. To test the functionality of MSC-EMs from early and late induction time points, we compared the first cultures to those initiated after 2 months by investigating their clonality and immunomodulatory capacity. Methods We analyzed the clonal composition of MSC-EM cultures by umbilical cord piece transduction using integrating lentiviral vectors harboring genetic barcodes assessed by high-throughput sequencing. We investigated the transcriptome of these cultures by microarrays. Finally, the secretome was analyzed by multiplexed ELISAs, in vitro assays, and in vivo in mice. Results DNA barcode analysis showed polyclonal MSC-EMs even after months of induction cycles. A transcriptome and secretome analyses of early and late MSC cultures showed only minor changes over time. However, upon activation with TNF-α and IFN-γ, cells from both induction time points produced a multitude of immunomodulatory cytokines. Interestingly, the later induced MSC-EMs produced higher amounts of cytokines. To test whether the different cytokine levels were in a therapeutically relevant range, we used conditioned medium (CM) in an in vitro MLR and an in vivo killing assay. CM from late induced MSC-EMs was at least as immune inhibitory as CM from early induced MSC-EMs. Conclusion Human umbilical cord maintains a microenvironment for the long-term induction of polyclonal and immune inhibitory active MSCs for months. Thus, our results would offer the possibility to drastically increase the number of therapeutically applicable MSCs for a substantial amount of patients.

scholarly journals The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3639 ◽  
Author(s):  
Giorgia Maroni ◽  
Daniele Panetta ◽  
Raffaele Luongo ◽  
Indira Krishnan ◽  
Federica La Rosa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Gene Dosage ◽  
Homeobox Gene ◽  
Fate Decision

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a “browning” effect in all fat tissues.

scholarly journals Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7688 ◽  
Author(s):  
Ancuta Jurj ◽  
Cecilia Pop-Bica ◽  
Ondrej Slaby ◽  
Cristina D. Ştefan ◽  
William C. Cho ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Recipient Cell ◽  
Cell Communication ◽  
Therapeutic Agents ◽  
Bioactive Molecules ◽  
Cellular Functions ◽  
Membrane Bound

Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.

scholarly journals Enhancing the Migration Ability of Mesenchymal Stromal Cells by Targeting the SDF-1/CXCR4 Axis

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Leah A. Marquez-Curtis ◽  
Anna Janowska-Wieczorek
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Surface Expression ◽  
Trophic Factors ◽  
Migration Ability ◽  
Therapeutic Benefits

Mesenchymal stromal cells (MSCs) are currently being investigated in numerous clinical trials of tissue repair and various immunological disorders based on their ability to secrete trophic factors and to modulate inflammatory responses. MSCs have been shown to migrate to sites of injury and inflammation in response to soluble mediators including the chemokine stromal cell-derived factor-(SDF-)1, but during in vitro culture expansion MSCs lose surface expression of key homing receptors particularly of the SDF-1 receptor, CXCR4. Here we review studies on enhancement of SDF-1-directed migration of MSCs with the premise that their improved recruitment could translate to therapeutic benefits. We describe our studies on approaches to increase the CXCR4 expression in in vitro-expanded cord blood-derived MSCs, namely, transfection, using the commercial liposomal reagent IBAfect, chemical treatment with the histone deacetylase inhibitor valproic acid, and exposure to recombinant complement component C1q. These methodologies will be presented in the context of other cell targeting and delivery strategies that exploit pathways involved in MSC migration. Taken together, these findings indicate that MSCs can be manipulated in vitro to enhance their in vivo recruitment and efficacy for tissue repair.

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