RESUMEN
Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.
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Cápsulas , Matriz Extracelular , Inmunomodulación , Células Madre Mesenquimatosas , Fibrosis Pulmonar , Animales , Matriz Extracelular/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones Endogámicos C57BL , Hidrogeles/química , Ratones , MasculinoRESUMEN
Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.
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Células Madre Mesenquimatosas , MicroARNs , Infarto del Miocardio , Nanopartículas , Infarto del Miocardio/terapia , Animales , Nanopartículas/química , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , MicroARNs/metabolismo , MicroARNs/genética , Masculino , Recuperación de la Función , Trasplante de Células Madre Mesenquimatosas/métodos , Humanos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ratones , Microburbujas , Ondas UltrasónicasRESUMEN
Mesenchymal stem cells (MSCs) are expected to be useful therapeutics in osteoarthritis (OA), the most common joint disorder characterized by cartilage degradation. However, evidence is limited with regard to cartilage repair in clinical trials because of the uncontrolled differentiation and weak cartilage-targeting ability of MSCs after injection. To overcome these drawbacks, here we synthesized CuO@MSN nanoparticles (NPs) to deliver Sox9 plasmid DNA (favoring chondrogenesis) and recombinant protein Bmp7 (inhibiting hypertrophy). After taking up CuO@MSN/Sox9/Bmp7 (CSB NPs), the expressions of chondrogenic markers were enhanced while hypertrophic markers were decreased in response to these CSB-engineered MSCs. Moreover, a cartilage-targeted peptide (designated as peptide W) was conjugated onto the surface of MSCs via a click chemistry reaction, thereby prolonging the residence time of MSCs in both the knee joint cavity of mice and human-derived cartilage. In a surgery-induced OA mouse model, the NP and peptide dual-modified W-CSB-MSCs showed an enhancing therapeutic effect on cartilage repair in knee joints compared with other engineered MSCs after intra-articular injection. Most importantly, W-CSB-MSCs accelerated cartilage regeneration in damaged cartilage explants derived from OA patients. Thus, this new peptide and NPs dual engineering strategy shows potential for clinical applications to boost cartilage repair in OA using MSC therapy.
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Diferenciación Celular , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Nanopartículas , Osteoartritis , Péptidos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Animales , Osteoartritis/terapia , Osteoartritis/patología , Nanopartículas/química , Humanos , Diferenciación Celular/efectos de los fármacos , Péptidos/química , Trasplante de Células Madre Mesenquimatosas/métodos , Condrogénesis/efectos de los fármacos , Ratones , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Cartílago Articular/patología , Cartílago Articular/efectos de los fármacos , Proteína Morfogenética Ósea 7/química , Proteína Morfogenética Ósea 7/farmacología , Ingeniería de Tejidos/métodos , Regeneración/efectos de los fármacosRESUMEN
BACKGROUND: Mesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms. METHODS: This prospective, self-controlled clinical study was conducted at Henan Provincial People's Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation. RESULTS: Forty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1ß, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy. CONCLUSION: UMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines. TRIAL REGISTRATION: The study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.
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Colitis Ulcerosa , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Cordón Umbilical , Humanos , Colitis Ulcerosa/terapia , Colitis Ulcerosa/patología , Femenino , Masculino , Adulto , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Cordón Umbilical/citología , Persona de Mediana Edad , Estudios Prospectivos , Citocinas/metabolismo , Citocinas/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Despite advancements in reconstructive procedures, ischemia-reperfusion (I/R) injury remains a significant challenge in reconstructive surgery, with mitochondrial dysfunction playing a pivotal role. Mitochondrial transplantation has emerged as a promising therapeutic strategy to address this issue. This study aims to evaluate the impact of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on skin flap I/R models in rats. MATERIAL AND METHODS: Twenty male rats underwent I/R injury on skin flaps, with or without mitochondrial transplantation administered via intravenous or subcutaneous routes. Analysis encompassed histopathology, inflammatory, apoptotic, oxidative stress, and hypoxia markers. RESULTS: Results revealed a reduction in inflammation, apoptosis, oxidative stress, and hypoxia in the transplantation group compared to controls. CONCLUSION: The findings suggest that umbilical cord mesenchymal stem cell-derived mitochondrial transplantation shows promise in enhancing flap viability and attenuating I/R injury, offering valuable insights for improved outcomes in reconstructive surgery. However, further exploration in larger animal models and refinement of delivery methods and dosage are warranted to fully elucidate its clinical translatability.
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Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas , Mitocondrias , Daño por Reperfusión , Cordón Umbilical , Animales , Masculino , Ratas , Trasplante de Células Madre Mesenquimatosas/métodos , Cordón Umbilical/citología , Mitocondrias/trasplante , Mitocondrias/metabolismo , Ratas Sprague-Dawley , Células Madre Mesenquimatosas , Colgajos Quirúrgicos/patología , Estrés Oxidativo , ApoptosisRESUMEN
BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects. CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.
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Exosomas , Células Madre Mesenquimatosas , Osteoartritis , Factor de Necrosis Tumoral alfa , Exosomas/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Osteoartritis/terapia , Osteoartritis/metabolismo , Tejido Adiposo/citología , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Cartílago Articular/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Cultivadas , HumanosRESUMEN
BACKGROUND: Emerging evidence has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cells (UC-MSCs) in chemotherapy-induced premature ovarian failure (POF). This study was designed to investigate the appropriate timing and molecular mechanism of UC-MSCs treatment for chemotherapy-induced POF. METHODS: Ovarian structure and function of mice were assessed every 3 days after injections with cyclophosphamide (CTX) and busulfan (BUS). UC-MSCs and UC-MSCs-derived extracellular vesicles (EVs) were infused into mice via the tail vein, respectively. Ovarian function was analyzed by follicle counts, the serum levels of hormones and ovarian morphology. The apoptosis and proliferation of ovarian granulosa cells were analyzed in vitro and in vivo. Label-free quantitative proteomics was used to detect the differentially expressed proteins in UC-MSC-derived EVs. RESULTS: After CTX/BUS injection, we observed that the ovarian function of POF mice was significantly deteriorated on day 9 after CTX/BUS infusion. TUNEL assay indicated that the number of apoptotic cells in the ovaries of POF mice was significantly higher than that in normal mice on day 3 after CTX/BUS injection. Transplantation of UC-MSCs on day 6 after CTX/BUS injection significantly improved ovarian function, enhanced proliferation and inhibited apoptosis of ovarian granulosa cells, whereas the therapeutic effect of UC-MSCs transplantation decreased on day 9, or day 12 after CTX/BUS injection. Moreover, EVs derived from UC-MSCs exerted similar therapeutic effects on POF. UC-MSCs-derived EVs could activate the PI3K/AKT signaling pathway and reduce ovarian granulosa cell apoptosis. Quantitative proteomics analysis revealed that clusterin (CLU) was highly expressed in the EVs of UC-MSCs. The supplementation of CLU proteins prevented ovarian granulosa cells from chemotherapy-induced apoptosis. Further mechanistic analysis showed that CLU-knockdown blocked the PI3K/AKT signaling and reversed the protective effects of UC-MSCs-derived EVs. CONCLUSIONS: Administration of UC-MSCs and UC-MSCs-derived EVs on day 6 of CTX/BUS injection could effectively improve the ovarian function of POF mice. UC-MSCs-derived EVs carrying CLU promoted proliferation and inhibited apoptosis of ovarian granulosa cells through activating the PI3K/AKT pathway. This study identifies a previously unrecognized molecular mechanism of UC-MSCs-mediated protective effects on POF, which pave the way for the use of cell-free therapeutic approach for POF.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Fosfatidilinositol 3-Quinasas , Insuficiencia Ovárica Primaria , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Cordón Umbilical , Femenino , Animales , Insuficiencia Ovárica Primaria/terapia , Insuficiencia Ovárica Primaria/metabolismo , Insuficiencia Ovárica Primaria/inducido químicamente , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Cordón Umbilical/citología , Clusterina/metabolismo , Apoptosis , Trasplante de Células Madre Mesenquimatosas/métodos , Ovario/metabolismo , Células de la Granulosa/metabolismo , Proliferación Celular , Busulfano/farmacologíaRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS. METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 106 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129. RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects. CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.
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Esclerosis Amiotrófica Lateral , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Proteómica , Trasplante Autólogo , Humanos , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/terapia , Esclerosis Amiotrófica Lateral/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteómica/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Femenino , Persona de Mediana Edad , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/líquido cefalorraquídeo , Anciano , Apolipoproteína A-I/líquido cefalorraquídeo , Apolipoproteína A-I/metabolismo , Adulto , Células de la Médula Ósea/metabolismo , Mapas de Interacción de ProteínasRESUMEN
AIMS AND OBJECTIVES: This study aimed to investigate the effects of Umbilical Cord Mesencymal Stem Cell Conditioning Medium (UC MSC-CM) administration on body weight recovery and the level of four molecular biomarkers, namely Superoxide Dismutase (SOD), vascular Endothelial Growth Factor (VEGF), C-Reactive Protein (CRP), and myostatin. MATERIALS AND METHODS: Secretome was injected intramuscularly twice at 1.5 mL (day 7 and 14) into the right thigh of high-dose, short-term galactose-induced aging rats. The data of day 7 (before) and day 21 (after the administration) were evaluated. The body weights and the four biomarkers were measured before (day 7) and after intervention (day 21). RESULTS: This study showed that the UC MSC-CM intramuscular administrations did not influence body weight regeneration. However, it could increase SOD and VEGF levels and decrease CRP and myostatin levels. CONCLUSION: Treatment with UC MSC-CM is a promising and potential agent in treating sarcopenia.
Résumé Buts et objectifs:Cette étude visait à examiner les effets de l'administration d'un milieu de conditionnement de cellules souches mésencéphaliques de cordon ombilical (UC MSC-CM) sur la récupération du poids corporel et le niveau de quatre biomarqueurs moléculaires, à savoir la superoxyde dismutase (SOD), le facteur de croissance endothéliale vasculaire (VEGF), la protéine C-réactive (CRP) et la myostatine.Matériels et méthodes:Le sécrétome (UC MSC-CM) a été injecté par voie intramusculaire deux fois à 1,5 ml (jour 7 et 14) dans la cuisse droite de rats vieillissant à forte dose et à court terme induits par le galactose. Les données du jour 7 (avant) et du jour 21 (après l'administration) ont été évaluées. Le poids corporel et les quatre biomarqueurs ont été mesurés avant (jour 7) et après l'intervention (jour 21).Résultats:Cette étude a montré que les administrations intramusculaires de CSM-CM d'UC n'ont pas influencé la régénération du poids corporel. Cependant, elle a pu augmenter les niveaux de SOD et de VEGF et diminuer les niveaux de CRP et de myostatine.Conclusion:Le traitement par UC MSC-CM est un agent prometteur et potentiel dans le traitement de la sarcopénie.
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Biomarcadores , Proteína C-Reactiva , Células Madre Mesenquimatosas , Miostatina , Superóxido Dismutasa , Factor A de Crecimiento Endotelial Vascular , Animales , Ratas , Biomarcadores/metabolismo , Biomarcadores/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína C-Reactiva/metabolismo , Superóxido Dismutasa/metabolismo , Miostatina/metabolismo , Masculino , Sarcopenia/metabolismo , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismo , Medios de Cultivo Condicionados/farmacología , Cordón Umbilical/citología , Peso Corporal , Inyecciones Intramusculares , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA), a rare but life-threatening systemic vasculitis, is distinguished by marked eosinophilia and presents with diverse symptoms, including asthma, cutaneous purpura, ecchymosis, skin necrosis, cardiac lesions, peripheral neuropathy, and necrotizing vasculitis. The etiology of EGPA involves a complex interaction among humoral, adaptive, innate, and allergic immune responses. Standard treatment employs prolonged high-dose glucocorticoid therapy, which is critical for survival; however, some patients' symptoms cannot be relieved. CASE REPORT: This case report details the medical management of an 11-year-old patient with EGPA, who was at risk of bilateral lower limb amputation due to differential arterial occlusion and severe, necrotizing vasculitis-induced gangrene in both feet. Treatment modalities administered included systemic infusion of Umbilical Cord Mesenchymal Stem Cells (UC-MSCs), targeted gastrocnemius muscle injections, and application of a Placenta-Derived Mesenchymal Stem Cells (PD-MSCs) hydrogel. RESULTS: After receiving a four-month regimen of allogeneic mesenchymal stem cell therapy via intravenous and local administration, the patient showed normalized eosinophil counts, reestablished blood flow in the dorsal arteries, and marked improvement in foot ulcerations. CONCLUSION: Mesenchymal stem cell therapy is a promising option for severe EGPA cases refractory to glucocorticoids.
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Gangrena , Granulomatosis con Poliangitis , Extremidad Inferior , Trasplante de Células Madre Mesenquimatosas , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Gangrena/terapia , Gangrena/etiología , Gangrena/patología , Niño , Extremidad Inferior/patología , Granulomatosis con Poliangitis/terapia , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/patología , Masculino , Femenino , Células Madre Mesenquimatosas/citologíaRESUMEN
BACKGROUND: Articular cartilage degeneration can result from injury, age, or arthritis, causing significant joint pain and disability without surgical intervention. Currently, the only FDA cell-based therapy for articular cartilage injury is Autologous Chondrocyte Implantation (ACI); however, this procedure is costly, time-intensive, and requires multiple treatments. Mesenchymal stromal cells (MSCs) are an attractive alternative autologous therapy due to their availability and ability to robustly differentiate into chondrocytes for transplantation with good safety profiles. However, treatment outcomes are variable due to donor-to-donor variability as well as intrapopulation heterogeneity and unstandardized MSC manufacturing protocols. Process improvements that reduce cell heterogeneity while increasing donor cell numbers with improved chondrogenic potential during expansion culture are needed to realize the full potential of MSC therapy. METHODS: In this study, we investigated the potential of MSC metabolic modulation during expansion to enhance their chondrogenic commitment by varying the nutrient composition, including glucose, pyruvate, glutamine, and ascorbic acid in culture media. We tested the effect of metabolic modulation in short-term (one passage) and long-term (up to seven passages). We measured metabolic state, cell size, population doubling time, and senescence and employed novel tools including micro-magnetic resonance relaxometry (µMRR) relaxation time (T2) to characterize the effects of AA on improved MSC expansion and chondrogenic potential. RESULTS: Our data show that the addition of 1 mM L-ascorbic acid-2-phosphate (AA) to cultures for one passage during MSC expansion prior to initiation of differentiation improves chondrogenic differentiation. We further demonstrate that AA treatment reduced the proportion of senescent cells and cell heterogeneity also allowing for long-term expansion that led to a > 300-fold increase in yield of MSCs with enhanced chondrogenic potential compared to untreated cells. AA-treated MSCs with improved chondrogenic potential showed a robust shift in metabolic profile to OXPHOS and higher µMRR T2 values, identifying critical quality attributes that could be implemented in MSC manufacturing for articular cartilage repair. CONCLUSIONS: Our results suggest an improved MSC manufacturing process that can enhance chondrogenic potential by targeting MSC metabolism and integrating process analytic tools during expansion.
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Cartílago Articular , Condrocitos , Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Cartílago Articular/metabolismo , Humanos , Condrocitos/metabolismo , Condrocitos/citología , Condrogénesis/efectos de los fármacos , Diferenciación Celular , Células Cultivadas , Proliferación Celular , Trasplante de Células Madre Mesenquimatosas/métodos , AnimalesRESUMEN
BACKGROUND: Burn trauma is one of the major causes of morbidity and mortality worldwide. The standard management of burn wounds consists of early debridement, dressing changes, surgical management, and split-thickness skin autografts (STSGs). However, there are limitations for the standard management that inclines us to find alternative treatment approaches, such as innovative cell-based therapies. We aimed to systematically review the different aspects of cell-based treatment approaches for burn wounds in clinical trials. METHODS: A systematic search through PubMed, Medline, Embase, and Cochrane Library databases was carried out using a combination of keywords, including "Cell transplantation", "Fibroblast", "Keratinocyte", "Melanocyte", or "Stem Cell" with "Burn", "Burn wound", or "Burn injury". Firstly, titles and abstracts of the studies existing in these databases until "February 2024" were screened. Then, the selected studies were read thoroughly, and considering the inclusion and exclusion criteria, final articles were included in this systematic review. Moreover, a manual search was performed through the reference lists of the included studies to minimize the risk of missing reports. RESULTS: Overall, 30 clinical trials with 970 patients were included in our study. Considering the type of cells, six studies used keratinocytes, nine used fibroblasts, eight used combined keratinocytes and fibroblasts, one study used combined keratinocytes and melanocytes, five used combined keratinocytes and fibroblasts and melanocytes, and one study used mesenchymal stem cells (MSCs). Evaluation of the preparation type in these studies showed that cultured method was used in 25 trials, and non-cultured method in 5 trials. Also, the graft type of 17 trials was allogeneic, and of 13 other trials was autologous. CONCLUSIONS: Our study showed that employing cell-based therapies for the treatment of burn wounds have significant results in clinical studies and are promising approaches that can be considered as alternative treatments in many cases. However, choosing appropriate cell-based treatment for each burn wound is essential and depends on the situation of each patient.
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Quemaduras , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Quemaduras/terapia , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Ensayos Clínicos como Asunto , Queratinocitos/citología , Queratinocitos/trasplante , Trasplante de Piel/métodos , Cicatrización de Heridas , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.
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Lesiones Traumáticas del Encéfalo , Trasplante de Células Madre Mesenquimatosas , Humanos , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/cirugía , Lesiones Traumáticas del Encéfalo/terapia , Masculino , Adulto , Femenino , Método Doble Ciego , Trasplante de Células Madre Mesenquimatosas/métodos , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Recent studies have highlighted the potential of Mesenchymal Stem Cells (MSCs) as an alternative treatment for Alopecia Areata (AA) due to their immunosuppressive properties. While MSCs have shown promise in cell experiments, their effectiveness in vivo remains uncertain. This study aims to validate local administration of MSC therapy's efficacy in AA treatment through animal experiments. AA was induced through Interferon-gamma (IFN-γ) administration in mice, and MSC treatment (MSCT)'s effects were assessed visually and through tissue analysis. The MSC-treated group showed more hair regrowth compared to the control (CTL) group. MSCT notably reduced local inflammatory cytokines (JAK1, JAK2, STAT1, STAT3, IFN-γR, IL-1ß, IL-16, IL-17α, and IL-18) in AA-induced mice's skin, but systemic cytokine levels remained unchanged. Furthermore, MSC treatment normalized the expression of Wnt/ß-catenin signaling pathway genes (LEF1 and ß-catenin) and growth factors (FGF7 and FGF2), which are crucial for hair cycle regulation. This study lays the groundwork for further exploring MSCs as a potential treatment for AA, but more research is needed to fully understand their therapeutic potential.
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Alopecia Areata , Citocinas , Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Alopecia Areata/terapia , Alopecia Areata/metabolismo , Ratones , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Citocinas/metabolismo , Vía de Señalización Wnt , Interferón gamma/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Femenino , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Factor de Unión 1 al Potenciador Linfoide/genéticaRESUMEN
Acute kidney injury (AKI) is widely recognized as a precursor to the onset or rapid progression of chronic kidney disease (CKD). However, there is currently no effective treatment available for AKI, underscoring the urgent need for the development of new strategies to improve kidney function. Human placental mesenchymal stromal cells (hpMSCs) were isolated from donor placentas, cultured, and characterized with regard to yield, viability, flow cytometry, and potency. To mimic AKI and its progression to CKD in a rat model, a dedicated sensitive non-clinical bilateral kidney ischemia-reperfusion injury (IRI) model was utilized. The experimental group received 3 × 105 hpMSCs into each kidney, while the control group received IRI and saline and the untreated group received IRI only. Urine, serum, and kidney tissue samples were collected over a period of 28 days. The hpMSCs exhibited consistent yields, viability, and expression of mesenchymal lineage markers, and were also shown to suppress T cell proliferation in a dose-dependent manner. To ensure optimal donor selection, manufacturing optimization, and rigorous quality control, the rigorous Good Manufacturing Practice (GMP) conditions were utilized. The results indicated that hpMSCs increased rat survival rates and improved kidney function by decreasing serum creatinine, urea, potassium, and fractionated potassium levels. Furthermore, the study demonstrated that hpMSCs can prevent the initial stages of kidney structural fibrosis and improve kidney function in the early stages by mitigating late interstitial fibrosis and tubular atrophy. Additionally, a robust manufacturing process with consistent technical parameters was established.
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Lesión Renal Aguda , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Insuficiencia Renal Crónica , Lesión Renal Aguda/terapia , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/patología , Humanos , Ratas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Femenino , Embarazo , Trasplante de Células Madre Mesenquimatosas/métodos , Placenta/citología , Daño por Reperfusión/terapia , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Modelos Animales de Enfermedad , Riñón/patología , Ratas Sprague-Dawley , Masculino , Progresión de la EnfermedadRESUMEN
OBJECTIVE: To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modulate periodontal bone repair through the hydroxylase domain-containing protein 2 (PHD2)/hypoxia- inducible factor-1 (HIF-1) signalling pathway in response to inflammatory conditions. METHODS: Osteogenic differentiation of PHD2 shRNA-modified BMMSCs and the possible mechanism were explored in an inflammatory microenvironment stimulated by porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in vitro. The effect of PHD2 gene-modified BMMSCs on periodontal bone loss was evaluated with experimental periodontitis. RESULTS: Pg-LPS stimulation greatly impaired the osteogenic differentiation of BMMSCs, whereas the silence of PHD2 significantly enhanced the osteogenesis of BMMSCs. More importantly, increased level of vascular endothelial growth factor (VEGF) was detected under Pg-LPS stimulation, which was verified to be associated with the augmented osteogenesis. In experimental periodontitis, PHD2-modified BMMSCs transplantation elevated osteogenic parameters and the expression of VEGF in periodontal tissue. CONCLUSION: This study highlighted that PHD2 gene silencing could be a feasible approach to combat inflammatory bone loss by rescuing the dysfunction of seed cells.
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Prolina Dioxigenasas del Factor Inducible por Hipoxia , Células Madre Mesenquimatosas , Osteogénesis , ARN Interferente Pequeño , Animales , ARN Interferente Pequeño/genética , Osteogénesis/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Porphyromonas gingivalis , Periodontitis/terapia , Periodontitis/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Diferenciación Celular , Lipopolisacáridos , Pérdida de Hueso Alveolar , Ratones , Masculino , Células de la Médula Ósea , Regeneración Ósea/genéticaRESUMEN
BACKGROUND: Mesenchymal Stromal Cells (MSCs) are the preferred candidates for therapeutics as they possess multi-directional differentiation potential, exhibit potent immunomodulatory activity, are anti-inflammatory, and can function like antimicrobials. These capabilities have therefore encouraged scientists to undertake numerous preclinical as well as a few clinical trials to access the translational potential of MSCs in disease therapeutics. In spite of these efforts, the efficacy of MSCs has not been consistent-as is reflected in the large variation in the values of outcome measures like survival rates. Survival rate is a resultant of complex cascading interactions that not only depends upon upstream experimental factors like dosage, time of infusion, type of transplant, etc.; but is also dictated, post-infusion, by intrinsic host specific attributes like inflammatory microniche including proinflammatory cytokines and alarmins released by the damaged host cells. These complex interdependencies make a researcher's task of designing MSC transfusion experiments challenging. METHODS: In order to identify the rules and associated attributes that influence the final outcome (survival rates) of MSC transfusion experiments, we decided to apply machine learning techniques on manually curated data collected from available literature. As sepsis is a multi-faceted condition that involves highly dysregulated immune response, inflammatory environment and microbial invasion, sepsis can be an efficient model to verify the therapeutic effects of MSCs. We therefore decided to implement rule-based classification models on data obtained from studies involving interventions of MSCs in sepsis preclinical models. RESULTS: The rules from the generated graph models indicated that survival rates, post-MSC-infusion, are influenced by factors like source, dosage, time of infusion, pre-Interleukin-6 (IL-6)/ Tumour Necrosis Factor- alpha (TNF-α levels, etc. CONCLUSION: This approach provides important information for optimization of MSCs based treatment strategies that may help the researchers design their experiments.
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Aprendizaje Automático , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Sepsis , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Humanos , Sepsis/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , AnimalesRESUMEN
Induced pluripotent stem cells (iPSCs) are a promising in vitro model for drug-screening and precision-based psychiatry for the treatment of major depressive disorders (MDD). In this chapter, we explore different uses for iPSC technology, three-dimensional (3D) organoids models, and mesenchymal stem cells therapy in MDD, as well their potential and limitations.
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Trastorno Depresivo Mayor , Células Madre Pluripotentes Inducidas , Organoides , Humanos , Células Madre Pluripotentes Inducidas/citología , Trastorno Depresivo Mayor/terapia , Organoides/metabolismo , Animales , Trasplante de Células Madre Mesenquimatosas/métodos , Diferenciación CelularRESUMEN
Cell therapy has emerged as one of the most promising approaches to treating disease in recent decades. The application of stem cells in anti-tumor therapy is determined by their varying capacity for proliferation, migration, and differentiation. These capacities are derived from different sources. The use of stem cell carriers in cancer treatment is justified by the following three reasons: (I) shield therapeutic agents from swift biological deterioration; (II) reduce systemic side effects; and (III) increase local therapeutic levels since stem cells have an innate ability to target tumors. The quantity of stem cells confined to the tumor microenvironment determines this system's anti-tumor activity. Nevertheless, there are limitations to the use of different types of stem cells. When immune cells are used in cell therapy, it may lead to cytokine storms and improper reactions to self-antigens. Furthermore, the use of stem cells may result in cancer. Additionally, after an intravenous injection, cells could not migrate to the injury location. Exosomes derived from different cells were thus proposed as possible therapeutic options. Exosomes are becoming more and more well-liked because of their small size, biocompatibility, and simplicity in storage and separation. A number of investigations have shown that adding various medications and microRNAs to exosomes may enhance their therapeutic effectiveness. Thus, it is essential to evaluate studies looking into the therapeutic effectiveness of encapsulated exosomes. In this review, we looked at studies on encapsulated exosomes' use in regenerative medicine and the treatment of cancer. The results imply that the therapeutic potential increases when encapsulated exosomes are used rather than intact exosomes. Therefore, in order to optimize the effectiveness of the treatment, it is advised to implement this technique in accordance with the kind of therapy.
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Vesículas Extracelulares , Hidrogeles , Células Madre Mesenquimatosas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/patología , Células Madre Mesenquimatosas/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Animales , Exosomas/metabolismo , Microambiente Tumoral , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient's life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field.