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  1. Benchtop Isolation and Characterisation of Small Extracellular Vesicles from Human Mesenchymal Stem Cells
    Tan KL, Chia WC, How CW, Tor YS, Show PL, Looi QHD, et al.
    Mol Biotechnol, 2021 Sep;63(9):780-791.
    PMID: 34061307 DOI: 10.1007/s12033-021-00339-2
    The objective of this study is to develop a simple protocol to isolate and characterise small extracellular vesicles (sEVs) from human umbilical cord-derived MSCs (hUC-MSCs). hUC-MSCs were characterised through analysis of morphology, immunophenotyping and multidifferentiation ability. SEVs were successfully isolated by ultrafiltration from the conditioned medium of hUC-MSCs. The sEVs' size distribution, intensity within a specific surface marker population were measured with zetasizer or nanoparticle tracking analysis. The expression of surface and internal markers of sEVs was also assessed by western blotting. Morphology of hUC-MSCs displayed as spindle-shaped, fibroblast-like adherent cells. Phenotypic analysis by flow cytometry revealed that hUC-MSCs expressed MSC surface marker, including CD90, CD73, CD105, CD44 and exhibited the capacity for osteogenic, adipogenic and chondrogenic differentiation. Populations of sEVs with CD9, CD63 and CD81 positive were detected with size distribution in the diameter of 63.2 to 162.5 nm. Typical sEVs biomarkers such as CD9, CD63, CD81, HSP70 and TSG101 were also detected with western blotting. Our study showed that sEVs from hUC-MSCs conditioned medium were successfully isolated and characterised. Downstream application of hUC-MSCs-sEVs will be further explored.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  2. Fulltext Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System
    Yeo GEC, Ng MH, Nordin FB, Law JX
    Int J Mol Sci, 2021 May 27;22(11).
    PMID: 34072224 DOI: 10.3390/ijms22115749
    Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  3. In Vitro Methods to Evaluate the Effects of Mesenchymal Stem Cells on TGF-β1-Induced Pulmonary Fibrosis
    Lan YW, Chen CM, Chong KY
    Methods Mol Biol, 2021;2269:83-92.
    PMID: 33687673 DOI: 10.1007/978-1-0716-1225-5_6
    A co-culture model of mesenchymal stem cells (MSCs) and fibroblasts is an efficient and rapid method to evaluate the anti-fibrotic effects of MSCs-based cell therapy. Transforming growth factor (TGF)-β1 plays a key role in promotion of fibroblast activation and differentiation which can induce collagen deposition, increase ECM production in lung tissue, eventually resulted in pulmonary fibrosis. Here, we use this co-culture system and examine the ECM production in activated fibroblasts by western blot and quantitative real-time analysis to understand the therapeutic effects of MSCs.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  4. Fulltext Collagen type I promotes osteogenic differentiation of amniotic membrane-derived mesenchymal stromal cells in basal and induction media
    Akhir HM, Teoh PL
    Biosci Rep, 2020 12 23;40(12).
    PMID: 33245097 DOI: 10.1042/BSR20201325
    Collagen has been widely shown to promote osteogenesis of bone marrow mesenchymal stromal cells (BM-MSCs). Due to the invasive procedure of obtaining BM-MSCs, MSCs from other tissues have emerged as a promising alternative for regenerative therapy. MSCs originated from different sources, exhibiting different differentiation potentials. Therefore, the applicability of collagen type I (COL), combining with amniotic membrane (AM)-MSCs was examined through proliferation and differentiation assays together with the expression of surface markers and genes associated with stemness and differentiation under basal or induction conditions. No increase in cell growth was observed because AM-MSCs might be directed toward spontaneous osteogenesis. This was evidenced by the calcium deposition and elevated expression of osteogenic genes when AM-MSCs were cultured in collagen plate with basal media. Under the osteogenic condition, reciprocal expression of OCN and CEBPA suggested a shift toward adipogenesis. Surprisingly, adipogenic genes were not elevated upon adipogenic induction, although oil droplets deposition was observed. In conclusion, our findings demonstrated that collagen causes spontaneous osteogenesis in AM-MSCs. However, the presence of exogenous inductors could shift the direction of adipo-osteogenic gene regulatory network modulated by collagen.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  5. Fulltext Therapeutic Potential of Bama Pig Adipose-Derived Mesenchymal Stem Cells for the Treatment of Carbon Tetrachloride-Induced Liver Fibrosis
    Wu X, Zhang S, Lai J, Lu H, Sun Y, Guan W
    Exp Clin Transplant, 2020 12;18(7):823-831.
    PMID: 33349209 DOI: 10.6002/ect.2020.0108
    OBJECTIVES: Liver fibrosis is inevitable in the healing process of liver injury. Liver fibrosis will develop into liver cirrhosis unless the damaging factors are removed. This study investigated the potential therapy of Bama pig adipose-derived mesenchymal stem cells in a carbon tetrachloride-induced liver fibrosis Institute of Cancer Research strain mice model.

    MATERIALS AND METHODS: Adipose-derived mesenchymal stem cells were injected intravenously into the tails of mice of the Institute of Cancer Research strain that had been treated with carbon tetrachloride for 4 weeks. Survival rate, migration, and proliferation of adipose-derived mesenchymal stem cells in the liver were observed by histochemistry, fluorescent labeling, and serological detection.

    RESULTS: At 1, 2, and 3 weeks after adipose-derived mesenchymal stem cell injection, liver fibrosis was significantly ameliorated. The injected adipose-derived mesenchymal stem cells had hepatic differentiation potential in vivo, and the survival rate of adipose-derived mesenchymal stem cells declined over time.

    CONCLUSIONS: The findings in this study confirmed that adipose-derived mesenchymal stem cells derived from the Bama pig can be used in the treatment of liver fibrosis, and the grafted adipose-derived mesenchy-mal stem cells can migrate, survive, and differentiate into hepatic cells in vivo.

    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  6. Fulltext Decoding the differentiation of mesenchymal stem cells into mesangial cells at the transcriptomic level
    Wong CY, Chang YM, Tsai YS, Ng WV, Cheong SK, Chang TY, et al.
    BMC Genomics, 2020 Jul 07;21(1):467.
    PMID: 32635896 DOI: 10.1186/s12864-020-06868-5
    BACKGROUND: Mesangial cells play an important role in the glomerulus to provide mechanical support and maintaine efficient ultrafiltration of renal plasma. Loss of mesangial cells due to pathologic conditions may lead to impaired renal function. Mesenchymal stem cells (MSC) can differentiate into many cell types, including mesangial cells. However transcriptomic profiling during MSC differentiation into mesangial cells had not been studied yet. The aim of this study is to examine the pattern of transcriptomic changes during MSC differentiation into mesangial cells, to understand the involvement of transcription factor (TF) along the differentiation process, and finally to elucidate the relationship among TF-TF and TF-key gene or biomarkers during the differentiation of MSC into mesangial cells.

    RESULTS: Several ascending and descending monotonic key genes were identified by Monotonic Feature Selector. The identified descending monotonic key genes are related to stemness or regulation of cell cycle while ascending monotonic key genes are associated with the functions of mesangial cells. The TFs were arranged in a co-expression network in order of time by Time-Ordered Gene Co-expression Network (TO-GCN) analysis. TO-GCN analysis can classify the differentiation process into three stages: differentiation preparation, differentiation initiation and maturation. Furthermore, it can also explore TF-TF-key genes regulatory relationships in the muscle contraction process.

    CONCLUSIONS: A systematic analysis for transcriptomic profiling of MSC differentiation into mesangial cells has been established. Key genes or biomarkers, TFs and pathways involved in differentiation of MSC-mesangial cells have been identified and the related biological implications have been discussed. Finally, we further elucidated for the first time the three main stages of mesangial cell differentiation, and the regulatory relationships between TF-TF-key genes involved in the muscle contraction process. Through this study, we have increased fundamental understanding of the gene transcripts during the differentiation of MSC into mesangial cells.

    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  7. Fulltext 3D Culture of MSCs on a Gelatin Microsphere in a Dynamic Culture System Enhances Chondrogenesis
    Sulaiman S, Chowdhury SR, Fauzi MB, Rani RA, Yahaya NHM, Tabata Y, et al.
    Int J Mol Sci, 2020 Apr 13;21(8).
    PMID: 32294921 DOI: 10.3390/ijms21082688
    Recent advancement in cartilage tissue engineering has explored the potential of 3D culture to mimic the in vivo environment of human cartilaginous tissue. Three-dimensional culture using microspheres was described to play a role in driving the differentiation of mesenchymal stem cells to chondrocyte lineage. However, factors such as mechanical agitation on cell chondrogenesis during culture on the microspheres has yet to be elucidated. In this study, we compared the 2D and 3D culture of bone-marrow-derived mesenchymal stem cells (BMSCs) on gelatin microspheres (GMs) in terms of MSC stemness properties, immune-phenotype, multilineage differentiation properties, and proliferation rate. Then, to study the effect of mechanical agitation on chondrogenic differentiation in 3D culture, we cultured BMSCs on GM (BMSCs-GM) in either static or dynamic bioreactor system with two different mediums, i.e., F12: DMEM (1:1) + 10% FBS (FD) and chondrogenic induction medium (CIM). Our results show that BMSCs attached to the GM surface and remained viable in 3D culture. BMSCs-GM proliferated faster and displayed higher stemness properties than BMSCs on a tissue culture plate (BMSCs-TCP). GMs also enhanced the efficiency of in-vitro chondrogenesis of BMSCs, especially in a dynamic culture with higher cell proliferation, RNA expression, and protein expression compared to that in a static culture. To conclude, our results indicate that the 3D culture of BMSCs on gelatin microsphere was superior to 2D culture on a standard tissue culture plate. Furthermore, culturing BMSCs on GM in dynamic culture conditions enhanced their chondrogenic differentiation.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  8. Human umbilical cord-mesenchymal stem cells: a promising strategy for corneal epithelial regeneration
    Azmi SM, Salih M, Abdelrazeg S, Roslan FF, Mohamed R, Tan JJ, et al.
    Regen Med, 2020 03;15(3):1381-1397.
    PMID: 32253974 DOI: 10.2217/rme-2019-0103
    Aim: As a strategy to improve the outcome of ex vivo cultivated corneal epithelial transplantation, the role of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) is investigated in promoting corneal epithelial growth and functions. Materials & methods: Human telomerase-immortalized corneal epithelial cells were characterized and its functions evaluated by scratch migration assay, cellular senescence, HLA expression and spheres formation with hUC-MSC. Results: Expression of corneal epithelial markers was influenced by the duration and method of co-culture. Indirect co-culture improved cellular migration and delayed senescence when treated after 3 and 5 days. hUC-MSC downregulated expression of HLA Class I and II in IFN-γ-stimulated human telomerase-immortalized corneal epithelial cells. Conclusion: hUC-MSC promote corneal epithelial growth and functions after treatment with hUC-MSC.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  9. Fulltext Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects
    Sarmadi VH, Ahmadloo S, Boroojerdi MH, John CM, Al-Graitte SJR, Lawal H, et al.
    Cell Transplant, 2020 2 7;29:963689719885077.
    PMID: 32024378 DOI: 10.1177/0963689719885077
    Treatment of leukemia has become much difficult because of resistance to the existing anticancer therapies. This has thus expedited the search for alternativ therapies, and one of these is the exploitation of mesenchymal stem cells (MSCs) towards control of tumor cells. The present study investigated the effect of human umbilical cord-derived MSCs (UC-MSCs) on the proliferation of leukemic cells and gauged the transcriptomic modulation and the signaling pathways potentially affected by UC-MSCs. The inhibition of growth of leukemic tumor cell lines was assessed by proliferation assays, apoptosis and cell cycle analysis. BV173 and HL-60 cells were further analyzed using microarray gene expression profiling. The microarray results were validated by RT-qPCR and western blot assay for the corresponding expression of genes and proteins. The UC-MSCs attenuated leukemic cell viability and proliferation in a dose-dependent manner without inducing apoptosis. Cell cycle analysis revealed that the growth of tumor cells was arrested at the G0/G1 phase. The microarray results identified that HL-60 and BV173 share 35 differentially expressed genes (DEGs) (same expression direction) in the presence of UC-MSCs. In silico analysis of these selected DEGs indicated a significant influence in the cell cycle and cell cycle-related biological processes and signaling pathways. Among these, the expression of DBF4, MDM2, CCNE2, CDK6, CDKN1A, and CDKN2A was implicated in six different signaling pathways that play a pivotal role in the anti-tumorigenic activity exerted by UC-MSCs. The UC-MSCs perturbate the cell cycle process of leukemic cells via dysregulation of tumor suppressor and oncogene expression.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  10. Sulfur and nitrogen containing plasma polymers reduces bacterial attachment and growth
    Siow KS, Abdul Rahman AS, Ng PY, Majlis BY
    Mater Sci Eng C Mater Biol Appl, 2020 Feb;107:110225.
    PMID: 31761201 DOI: 10.1016/j.msec.2019.110225
    Role of sulfur (S) and nitrogen (N) groups in promoting cell adhesion or commonly known as biocompatibility, is well established, but their role in reducing bacterial attachment and growth is less explored or not well-understood. Natural sulfur-based compounds, i.e. sulfide, sulfoxide and sulfinic groups, have shown to inhibit bacterial adhesion and biofilm formation. Hence, we mimicked these surfaces by plasma polymerizing thiophene (ppT) and air-plasma treating this ppT to achieve coatings with S of similar oxidation states as natural compounds (ppT-air). In addition, the effects of these N and S groups from ppT-air were also compared with the biocompatible amine-amide from n-heptylamine plasma polymer. Crystal violet assay and live and dead fluorescence staining of E. coli and S. aureus showed that all the N and S coated surfaces generated, including ppHA, ppT and ppT-air, produced similarly potent, growth reduction of both bacteria by approximately 65% at 72 h compared to untreated glass control. The ability of osteogenic differentiation in Wharton's jelly mesenchymal stem cells (WJ-MSCs) were also used to test the cell biocompatibility of these surfaces. Alkaline phosphatase assay and scanning electron microscopy imaging of these WJ-MSCs growths indicated that ppHA, and ppT-air were cell-friendly surfaces, with ppHA showing the highest osteogenic activity. In summary, the N and S containing surfaces could reduce bacteria growth while promoting mammalian cell growth, thus serve as potential candidate surfaces to be explored further for biomaterial applications.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  11. Fulltext Protective effects of stem cells from human exfoliated deciduous teeth derived conditioned medium on osteoarthritic chondrocytes
    Muhammad SA, Nordin N, Hussin P, Mehat MZ, Abu Kasim NH, Fakurazi S
    PLoS One, 2020;15(9):e0238449.
    PMID: 32886713 DOI: 10.1371/journal.pone.0238449
    Treatment of osteoarthritis (OA) is still a major clinical challenge due to the limited inherent healing capacity of cartilage. Recent studies utilising stem cells suggest that the therapeutic benefits of these cells are mediated through the paracrine mechanism of bioactive molecules. The present study evaluates the regenerative effect of stem cells from human exfoliated deciduous teeth (SHED) conditioned medium (CM) on OA chondrocytes. The CM was collected after the SHED were cultured in serum-free medium (SFM) for 48 or 72 h and the cells were characterised by the expression of MSC and pluripotency markers. Chondrocytes were stimulated with interleukin-1β and treated with the CM. Subsequently, the expression of aggrecan, collagen type 2 (COL 2), matrix metalloproteinase-13 (MMP-13), nuclear factor-kB (NF-kB) and the level of inflammatory and anti-inflammatory markers were evaluated. SHED expressed mesenchymal stromal cell surface proteins but were negative for haematopoietic markers. SHED also showed protein expression of NANOG, OCT4 and SOX2 with differential subcellular localisation. Treatment of OA chondrocytes with CM enhanced anti-inflammation compared to control cells treated with SFM. Furthermore, the expression of MMP-13 and NF-kB was significantly downregulated in stimulated chondrocytes incubated in CM. The study also revealed that CM increased the expression of aggrecan and COL 2 in OA chondrocytes compared to SFM control. Both CM regenerate extracellular matrix proteins and mitigate increased MMP-13 expression through inhibition of NF-kB in OA chondrocytes due to the presence of bioactive molecules. The study underscores the potential of CM for OA treatment.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  12. Understanding the multifaceted mechanisms of diabetic wound healing and therapeutic application of stem cells conditioned medium in the healing process
    Fui LW, Lok MPW, Govindasamy V, Yong TK, Lek TK, Das AK
    J Tissue Eng Regen Med, 2019 12;13(12):2218-2233.
    PMID: 31648415 DOI: 10.1002/term.2966
    Mesenchymal stem cells (MSCs) transplantation seems to be a promising new therapy for diabetic wound healing (DWH), and currently, arrays of MSCs from various sources ranging from umbilical, adipose to dental sources are available as a treatment modality for this disease. However, it now appears that only a fraction of transplanted cells actually assimilate and survive in host tissues suggesting that the major mechanism by which stem cells participate in tissue repair are most likely related to their secretome level. These include a wide range of growth factors, cytokines, and chemokines, which can be found from the conditioned medium (CM) used to culture the cells. Basic studies and preclinical work confirm that the therapeutic effect of CMs are comparable with the application of stem cells. This review describes in detail the wound healing process in diabetes and the cellular and biological factors that influence the process. Subsequently, through a comprehensive literature search of studies related to wound healing in diabetics, we aim to provide an overview of scientific merits of using MSCs-CM in the treatment of diabetic wound as well as the significant caveats, which restricts its potential use in clinical set-ups. To our best knowledge, this is one of the first review papers that collect the importance of stem cells as an alternative treatment to the DWH. We anticipate that the success of this treatment will have a significant clinical impact on diabetic wounds.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  13. Dental pulp stem cells therapy overcome photoreceptor cell death and protects the retina in a rat model of sodium iodate-induced retinal degeneration
    Alsaeedi HA, Koh AE, Lam C, Rashid MBA, Harun MHN, Saleh MFBM, et al.
    J. Photochem. Photobiol. B, Biol., 2019 Sep;198:111561.
    PMID: 31352000 DOI: 10.1016/j.jphotobiol.2019.111561
    Blindness and vision loss contribute to irreversible retinal degeneration, and cellular therapy for retinal cell replacement has the potential to treat individuals who have lost light sensitive photoreceptors in the retina. Retinal cells are well characterized in function, and are a subject of interest in cellular replacement therapy of photoreceptors and the retinal pigment epithelium. However, retinal cell transplantation is limited by various factors, including the choice of potential stem cell source that can show variability in plasticity as well as host tissue integration. Dental pulp is one such source that contains an abundance of stem cells. In this study we used dental pulp-derived mesenchymal stem cells (DPSCs) to mitigate sodium iodate (NaIO3) insult in a rat model of retinal degeneration. Sprague-Dawley rats were first given an intravitreal injection of 3 × 105 DPSCs as well as a single systemic administration of NaIO3 (40 mg/kg). Electroretinography (ERG) was performed for the next two months and was followed-up by histological analysis. The ERG recordings showed protection of DPSC-treated retinas within 4 weeks, which was statistically significant (* P ≤ .05) compared to the control. Retinal thickness of the control was also found to be thinner (*** P ≤ .001). The DPSCs were found integrated in the photoreceptor layer through immunohistochemical staining. Our findings showed that DPSCs have the potential to moderate retinal degeneration. In conclusion, DPSCs are a potential source of stem cells in the field of eye stem cell therapy due to its protective effects against retinal degeneration.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  14. Application of Ti3 C2 MXene Quantum Dots for Immunomodulation and Regenerative Medicine
    Rafieerad A, Yan W, Sequiera GL, Sareen N, Abu-El-Rub E, Moudgil M, et al.
    Adv Healthc Mater, 2019 08;8(16):e1900569.
    PMID: 31265217 DOI: 10.1002/adhm.201900569
    Inflammation is tightly linked to tissue injury. In regenerative medicine, immune activation plays a key role in rejection of transplanted stem cells and reduces the efficacy of stem cell therapies. Next-generation smart biomaterials are reported to possess multiple biologic properties for tissue repair. Here, the first use of 0D titanium carbide (Ti3 C2 ) MXene quantum dots (MQDs) for immunomodulation is presented with the goal of enhancing material-based tissue repair after injury. MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of human CD4+ IFN-γ+ T-lymphocytes (control 87.1 ± 2.0%, MQDs 68.3 ± 5.4%) while promoting expansion of immunosuppressive CD4+ CD25+ FoxP3+ regulatory T-cells (control 5.5 ± 0.7%, MQDs 8.5 ± 0.8%) in a stimulated lymphocyte population. Furthermore, MQDs are biocompatible with bone marrow-derived mesenchymal stem cells and induced pluripotent stem cell-derived fibroblasts. Finally, Ti3 C2 MQDs are incorporated into a chitosan-based hydrogel to create a 3D platform with enhanced physicochemical properties for stem cell delivery and tissue repair. This composite hydrogel demonstrates increased conductivity while maintaining injectability and thermosensitivity. These findings suggest that this new class of biomaterials may help bridge the translational gap in material and stem cell-based therapies for tissue repair and treatment of inflammatory and degenerative diseases.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  15. Genetically-modified human mesenchymal stem cells to express erythropoietin enhances differentiation into retinal photoreceptors: An in-vitro study
    Ding SLS, Koh AE, Kumar S, Ali Khan MS, Alzahrani B, Mok PL
    J. Photochem. Photobiol. B, Biol., 2019 Jun;195:33-38.
    PMID: 31060031 DOI: 10.1016/j.jphotobiol.2019.04.008
    Dysfunctional or death of retinal photoreceptors is an irreversible phenomenon that is closely associated with a broad range of retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD), resulting in successive loss of visual function and blindness. In search for viable treatment for retinal degenerative diseases, mesenchymal stem cells (MSCs) has demonstrated promising therapeutic capabilities to repair and replace damaged photoreceptor cells in both in vitro and in vivo conditions. Nevertheless, the dearth of MSC differentiation capacity into photoreceptors has limited its use in cell replacement therapy. Erythropoietin (EPO) has vital role in early neural retinal cell differentiation and demonstrated rescue potential on dying photoreceptor cells. Hence, we aimed to evaluate the differentiation capacity of MSCs into photoreceptor cells in the presence of human EPO protein. We derived the MSC from human Wharton's jelly of umbilical cord and transduced the cells with lentivirus particles encoding EPO and green fluorescent protein (GFP) as reporter gene. The transduced cells were selectively cultured and induced to differentiate into photoreceptors by exposing to photoreceptor differentiation cocktail. Our preliminary results showed that transduced cells exposed to induction medium had an enhanced differentiation capacity when compared to non-transduced cells. Our results demonstrated a novel strategy to increase the yield of in vitro photoreceptor differentiation and may be potentially useful in improving the efficiency of stem cell transplantation for ocular disorders.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  16. Mesenchymal stem cells facilitate cardiac differentiation in Sox2-expressing cardiac C-kit cells in coculture
    Leong YY, Ng WH, Umar Fuaad MZ, Ng CT, Ramasamy R, Lim V, et al.
    J Cell Biochem, 2019 06;120(6):9104-9116.
    PMID: 30548289 DOI: 10.1002/jcb.28186
    Stem cell therapy offers hope to reconstitute injured myocardium and salvage heart from failing. A recent approach using combinations of derived Cardiac-derived c-kit expressing cells (CCs) and mesenchymal stem cells (MSCs) in transplantation improved infarcted hearts with a greater functional outcome, but the effects of MSCs on CCs remain to be elucidated. We used a novel two-step protocol to clonogenically amplify colony forming c-kit expressing cells from 4- to 6-week-old C57BL/6N mice. This method yielded highly proliferative and clonogenic CCs with an average population doubling time of 17.2 ± 0.2, of which 80% were at the G1 phase. We identified two distinctly different CC populations based on its Sox2 expression, which was found to inversely related to their nkx2.5 and gata4 expression. To study CCs after MSC coculture, we developed micron-sized particles of iron oxide-based magnetic reisolation method to separate CCs from MSCs for subsequent analysis. Through validation using the sex and species mismatch CC-MSC coculture method, we confirmed that the purity of the reisolated cells was greater than 85%. In coculture experiment, we found that MSCs prominently enhanced Ctni and Mef2c expressions in Sox2 pos CCs after the induction of cardiac differentiation, and the level was higher than that of conditioned medium Sox2 pos CCs. However, these effects were not found in Sox2 neg CCs. Immunofluorescence labeling confirmed the presence of cardiac-like cells within Sox2 pos CCs after differentiation, identified by its cardiac troponin I and α-sarcomeric actinin expressions. In conclusion, this study shows that MSCs enhance CC differentiation toward cardiac myocytes. This enhancement is dependent on CC stemness state, which is determined by Sox2 expression.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  17. Fulltext Empowering Mesenchymal Stem Cells for Ocular Degenerative Disorders
    Ding SSL, Subbiah SK, Khan MSA, Farhana A, Mok PL
    Int J Mol Sci, 2019 Apr 10;20(7).
    PMID: 30974904 DOI: 10.3390/ijms20071784
    Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite the known therapeutic role and mechanisms of MSCs, low cell precision towards the targeted area and cell survivability at tissue needing repair often resulted in a disparity in therapeutic outcomes. In this review, we will discuss the current and feasible strategy options to enhance treatment outcomes with MSC therapy. We will review the application of various types of biomaterials and advances in nanotechnology, which have been employed on MSCs to augment cellular function and differentiation for improving treatment of visual functions. In addition, several modes of gene delivery into MSCs and the types of associated therapeutic genes that are important for modulation of ocular tissue function and repair will be highlighted.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  18. Comparative efficacy of stem cells and secretome in articular cartilage regeneration: a systematic review and meta-analysis
    Muhammad SA, Nordin N, Mehat MZ, Fakurazi S
    Cell Tissue Res, 2019 Feb;375(2):329-344.
    PMID: 30084022 DOI: 10.1007/s00441-018-2884-0
    Articular cartilage defect remains the most challenging joint disease due to limited intrinsic healing capacity of the cartilage that most often progresses to osteoarthritis. In recent years, stem cell therapy has evolved as therapeutic strategies for articular cartilage regeneration. However, a number of studies have shown that therapeutic efficacy of stem cell transplantation is attributed to multiple secreted factors that modulate the surrounding milieu to evoke reparative processes. This systematic review and meta-analysis aim to evaluate and compare the therapeutic efficacy of stem cell and secretome in articular cartilage regeneration in animal models. We systematically searched the PubMed, CINAHL, Cochrane Library, Ovid Medline and Scopus databases until August 2017 using search terms related to stem cells, cartilage regeneration and animals. A random effect meta-analysis of the included studies was performed to assess the treatment effects on new cartilage formation on an absolute score of 0-100% scale. Subgroup analyses were also performed by sorting studies independently based on similar characteristics. The pooled analysis of 59 studies that utilized stem cells significantly improved new cartilage formation by 25.99% as compared with control. Similarly, the secretome also significantly increased cartilage regeneration by 26.08% in comparison to the control. Subgroup analyses revealed no significant difference in the effect of stem cells in new cartilage formation. However, there was a significant decline in the effect of stem cells in articular cartilage regeneration during long-term follow-up, suggesting that the duration of follow-up is a predictor of new cartilage formation. Secretome has shown a similar effect to stem cells in new cartilage formation. The risk of bias assessment showed poor reporting for most studies thereby limiting the actual risk of bias assessment. The present study suggests that both stem cells and secretome interventions improve cartilage regeneration in animal trials. Graphical abstract ᅟ.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
  19. Guided evaluation and standardisation of mesenchymal stem cell culture conditions to generate conditioned medium favourable to cardiac c-kit cell growth
    Ng WH, Umar Fuaad MZ, Azmi SM, Leong YY, Yong YK, Ng AMH, et al.
    Cell Tissue Res, 2019 Feb;375(2):383-396.
    PMID: 30232595 DOI: 10.1007/s00441-018-2918-7
    Mesenchymal stem cells (MSCs) are known to secrete cardioprotective paracrine factors that can potentially activate endogenous cardiac c-kit cells (CCs). This study aims to optimise MSC growth conditions and medium formulation for generating the conditioned medium (CdM) to facilitate CC growth and expansion in vitro. The quality of MSC-CdM after optimisation of seeding density during MSC stabilisation and medium formulation used during MSC stimulation including glucose, ascorbic acid, serum and oxygen levels and the effects of treatment concentration and repeated CdM harvesting were assessed based on CC viability in vitro under growth factor- and serum-deprived condition. Our data showed that functional CdM can be produced from MSCs with a density of 20,000 cells/cm2, which were stimulated using high glucose (25 mM), ascorbic acid supplemented, serum-free medium under normoxic condition. The generated CdM, when applied to growth factor- and serum-deprived medium at 1:1 ratio, improved CC viability, migration and proliferation in vitro. Such an effect could further be augmented by generating CdM concentrates without compromising CC gene and protein expressions, while retaining its capability to undergo differentiation to form endothelial, smooth muscle and cardiomyocytes. Nevertheless, CdM could not be repeatedly harvested from the same MSC culture, as the protein content and its effect on CC viability deteriorated after the first harvest. In conclusion, this study provides a proof-of-concept strategy to standardise the production of CdM from MSCs based on rapid, stepwise assessment of CC viability, thus enabling production of CdM favourable to CC growth for in vitro or clinical applications.
    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism
  20. The effect of mesenchymal stem cell-secreted factors on airway epithelial repair
    Halim NS, Aizat WM, Yahaya BH
    Regen Med, 2019 01;14(1):15-31.
    PMID: 30566028 DOI: 10.2217/rme-2018-0020
    AIM: This study was aimed to investigate the effect of mesenchymal stem cell (MSC)-secreted factors on airway repair.

    MATERIALS & METHODS: An indirect in vitro coculture model of injured airway epithelium explant with MSCs was developed. LC-MS/MS analysis was performed to determine factors secreted by MSCs and their involvement in epithelium repair was evaluated by histopathological assessment.

    RESULTS: The identification of 54 of MSC proteins of which 44 of them were secretory/extracellular proteins. 43 of the secreted proteins were found to be involved in accelerating airway epithelium repair by stimulating the migratory, proliferative and differentiation abilities of the endogenous repair mechanisms. MSC-secreted proteins also initiated epithelial-mesenchymal transition process during early repair.

    CONCLUSION: MSC-secreted factors accelerated airway epithelial repair by stimulating the endogenous reparative and regenerative ability of lung cells.

    Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*
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