Immunomodulation and Regenerative Capacity of MSCs for Long-COVID.
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ABSTRACT:
SUBMITTER: Loke XY
PROVIDER: S-EPMC8625432 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases.
| S-EPMC6566837 | biostudies-literature
Project description:BackgroundInflammatory memory or trained immunity is a recently described process in immune and non-immune tissue resident cells, whereby previous exposure to inflammation mediators leads to a faster and stronger responses upon secondary challenge. Whether previous muscle injury is associated with altered responses to subsequent injury by satellite cells (SCs), the muscle stem cells, is not known.MethodsWe used a mouse model of repeated muscle injury, in which intramuscular cardiotoxin (CTX) injections were administered 50 days apart in order to allow for full recovery of the injured muscle before the second injury. The effect of prior injury on the phenotype, proliferation and regenerative potential of satellite cells following a second injury was examined in vitro and in vivo by immunohistochemistry, RT-qPCR and histological analysis.ResultsWe show that SCs isolated from muscle at 50 days post-injury (injury-experienced SCs (ieSCs)) enter the cell cycle faster and form bigger myotubes when cultured in vitro, compared to control SCs isolated from uninjured contralateral muscle. Injury-experienced SCs were characterized by the activation of the mTORC 1 signaling pathway, suggesting they are poised to activate sooner following a second injury. Consequently, upon second injury, SCs accumulate in greater numbers in muscle at 3 and 10 days after injury. These changes in SC phenotype and behavior were associated with accelerated muscle regeneration, as evidenced by an earlier appearance of bigger fibers and increased number of myonuclei per fiber at day 10 after the second injury.ConclusionsOverall, we show that skeletal muscle injury has a lasting effect on SC function priming them to respond faster to a subsequent injury. The ieSCs have long-term enhanced regenerative properties that contribute to accelerated regeneration following a secondary challenge.
| S-EPMC10496398 | biostudies-literature
Project description:With a robust rise in the number of COVID-19 cases, the World Health Organization (WHO) has declared COVID-19 as a pandemic on 11th March 2020. COVID-19 pandemic has invited global researchers from various biomedical and biotechnological researchers to plan various treatment modalities for combating this pandemic crisis. At present, there is the unavailability of specific treatment modality; however, researchers have thrown light into the exploration of mesenchymal stem cells (MSCs) to therapeutically perquisite in ameliorating immune-mediated progressive worsening in COVID-19 infected patients. Cellular therapy (CT) has revolutionized the treatment of untreatable diseases with a better clinical and functional outcome. Placenta, being considered as medical waste, contains a variety of stem cells, and hence placenta-derived MSCs (P-MSCs) owe potentiality for extrapolation to combat COVID-19 pandemic. The usage of P-MSCs in combating the COVID-19 pandemic has plausible challenges in terms of isolation, harvesting, expansion, characterization, and involvement of ethical concerns. This article provides an insight into dealing COVID-19 pandemic with P-MSCs as cell-based therapy embracing immunomodulatory and immune-privileged potentials and future prospects. Advocating prospective randomized controlled clinical trials ethically will concretely supplement for its efficacy and safety concerns.
| S-EPMC7937692 | biostudies-literature
Project description:Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC's immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV's immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.
| S-EPMC9108364 | biostudies-literature
Project description:White matter injury, consisting of loss of axons, myelin, and oligodendrocytes, is common in many neurological disorders and is believed to underlie several motor and sensory deficits. Remyelination is the process in which the insulative myelin sheath is restored to axons, thereby facilitating recovery from functional loss. Remyelination proceeds with oligodendrocyte precursor cells (OPCs) that differentiate into oligodendrocytes to synthesize the new myelin sheath after demyelination. This process is influenced by several factors, including trophic factors, inhibitory molecules in the lesion microenvironment, age of the subject, as well as the inflammatory response. Currently studied strategies that enhance remyelination consist of pharmacological approaches that directly induce OPC differentiation or using agents to neutralize the inhibitory microenvironment. Another strategy is to harness a reparative inflammatory response. This response, coordinated by central nervous system resident microglia and peripherally-derived infiltrating macrophages, has been shown to be important in the remyelination process. These innate immune cells perform important functions in remyelination, including the proteolysis and phagocytosis of inhibitory molecules present in the lesion microenvironment, the provision of trophic and metabolic factors to OPCs, in addition to iron handling capacity. Additionally, an initial pro-inflammatory phase followed by a regulatory/anti-inflammatory phase has been shown to be important for OPC proliferation and differentiation, respectively. This review will discuss the beneficial roles of macrophages/microglia in remyelination and discuss therapeutic strategies to obtain the optimal regenerative macrophage phenotype for enhanced remyelination.
| S-EPMC4873494 | biostudies-literature
Project description:BACKGROUND:Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied. METHODS:Inflammatory licensed MSCs were generated through priming with either IFN-? or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-?. Licensed MSCs were co-cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-?1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-?, IFN-?) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-? or poly I:C-primed MSCs was applied to IL-1?-stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-?, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes. RESULTS:IFN-?-primed MSCs had a superior ability to suppress T-cell proliferation compared to naïve MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naïve and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1?-stimulated chondrocytes. CONCLUSIONS:In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment.
| S-EPMC5883371 | biostudies-literature
Project description:Oral fibroblasts are speculated to exhibit superior healing capacity. We used scRNA-seq to investigate oral fibroblast heterogeneity in mouse and human palate tissues.
2022-12-19 | GSE217720 | GEO
Project description:RationaleLeukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration.ObjectiveMain objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes.Methods and resultsWe measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization, or cerebrovascular events) independently of each other, with a hazard ratio of 1.8 and 95% confidence interval of 1.1 to 2.0, and a hazard ratio of 2.1 and 95% confidence interval of 1.3 to 3.0, respectively, comparing Q1 to Q2-4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1) had the greatest risk of adverse outcomes (hazard ratio =3.5; 95% confidence interval, 1.7-7.1).ConclusionsAlthough shorter LTL is associated with decreased regenerative capacity, both LTL and circulating progenitor cell levels are independent and additive predictors of adverse cardiovascular outcomes in coronary artery disease patients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.
| S-EPMC5376244 | biostudies-literature
Project description:Involution of the thymus is accompanied by a decline in the number of thymic epithelial cells (TECs) and a severely restricted peripheral repertoire of T-cell specificities. TECs are essential for T-cell differentiation; they originate from a bipotent progenitor that gives rise to cells of cortical (cTEC) and medullary (mTEC) phenotypes, via compartment-specific progenitors. Upon acute selective near-total ablation during embryogenesis, regeneration of TECs fails, suggesting that losses from the pool of TEC progenitors are not compensated. However, it is unclear whether this is also true for the compartment-specific progenitors. The decline of cTECs is a prominent feature of thymic involution. Because cTECs support early stages of T-cell development and hence determine the overall lymphopoietic capacity of the thymus, it is possible that the lack of sustained regenerative capacity of cTEC progenitor cells underlies the process of thymic involution. Here, we examine this hypothesis by cell-type-specific conditional ablation of cTECs. Expression of the human diphtheria toxin receptor (hDTR) gene under the regulatory influence of the chemokine receptor Ccx-ckr1 gene renders cTECs sensitive to the cytotoxic effects of diphtheria toxin (DT). As expected, DT treatment of preadolescent and adult mice led to a dramatic loss of cTECs, accompanied by a rapid demise of immature thymocytes. Unexpectedly, however, the cTEC compartment regenerated after cessation of treatment, accompanied by the restoration of T-cell development. These findings provide the basis for the development of targeted interventions unlocking the latent regenerative potential of cTECs to counter thymic involution.
| S-EPMC3295321 | biostudies-literature
Project description:Scaffolds can be introduced as a source of tissue in reconstructive surgery and can help to improve wound healing. Amniotic membranes (AMs) as scaffolds for tissue engineering have emerged as promising biomaterials for surgical reconstruction due to their regenerative capacity, biocompatibility, gradual degradability, and availability. They also promote fetal-like scarless healing and provide a bioactive matrix that stimulates cell adhesion, migration, and proliferation. The aim of this study was to create a tissue-engineered AM-based implant for the repair of vesicovaginal fistula (VVF), a defect between the bladder and vagina caused by prolonged obstructed labor. Layers of AMs (with or without cross-linking) and electrospun poly-4-hydroxybutyrate (P4HB) (a synthetic, degradable polymer) scaffold were joined together by fibrin glue to produce a multilayer scaffold. Human vaginal fibroblasts were seeded on the different constructs and cultured for 28 days. Cell proliferation, cell morphology, collagen deposition, and metabolism measured by matrix metalloproteinase (MMP) activity were evaluated. Vaginal fibroblasts proliferated and were metabolically active on the different constructs, producing a distributed layer of collagen and proMMP-2. Cell proliferation and the amount of produced collagen were similar across different groups, indicating that the different AM-based constructs support vaginal fibroblast function. Cell morphology and collagen images showed slightly better alignment and organization on the un-cross-linked constructs compared to the cross-linked constructs. It was concluded that the regenerative capacity of AM does not seem to be affected by mechanical reinforcement with cross-linking or the addition of P4HB and fibrin glue. An AM-based implant for surgical repair of internal organs requiring load-bearing functionality can be directly translated to other types of surgical reconstruction of internal organs.
| S-EPMC10951947 | biostudies-literature