Human Mesenchymal Stem Cell Therapy Research Articles

Serum metabonomics reveal the effectiveness of human placental mesenchymal stem cell therapy for primary sclerosing cholangitis.

The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Using Mdr2-/- mice as a PSC model and Mdr2+/+ mice as controls, the efficacy of hP-MSC treatment was assessed based on liver pathology, liver enzymes, and inflammatory factors. Serum samples were collected for 12C-/13C-dansylation and DmPA labeling LC-MS analysis to investigate changes in metabolic pathways after hP-MSC treatment. Key metabolites and regulatory enzymes were validated by qRT-PCR and Western blotting. Potential biomarkers of hP-MSC efficacy were identified through correlation analysis and machine learning. Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, L-1-pyrroline-3-hydroxy-5-carboxylic acid, L-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC.

Serum metabolomics reveals the effectiveness of human placental mesenchymal stem cell therapy for Crohn's disease

Mesenchymal stem cell (MSC) therapy offers a promising cure for Crohn's disease (CD), however, its therapeutic effects vary significantly due to individual differences. Therefore, identifying easily detectable biomarkers is essential to assess the efficacy of MSC therapy. In this study, SAMP1/Yit mice were used as a model of CD, which develop spontaneous chronic ileitis, closely resembling the characteristics present in CD patients. Serum metabolic alterations during treatment were analyzed, through the application of differential 12C-/13C-dansylation labeling liquid chromatography-mass spectrometry. Based on the significant differences and time-varying trends of serum amine/phenol-containing metabolites abundance between the control group, the model group, and the treatment group, four serum biomarkers were ultimately screened for evaluating the efficacy of MSC treatment for CD, namely 4-hydroxyphenylpyruvate, 4-hydroxyphenylacetaldehyde, caffeate, and N-acetyltryptamine, whose abundances both increased in the serum of CD model mice and decreased after MSC treatment. These metabolic alterations were associated with tyrosine metabolism, which was validated by the dysregulation of related enzymes. The discovery of biomarkers may help to improve the targeting and effectiveness of treatment and provide innovative prospects for the clinical application of MSC for CD.

Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China

IntroductionAlport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem...

Intravenous human dental pulp-derived mesenchymal stem cell therapy for ischemic stroke in rats: an analysis of functional and ischemic brain areas outcomes

Cellular therapies have been implicated in treating and rehabilitating ischemic stroke (IS), involving the basic experimental and preclinical areas. Using mesenchymal stem cells (MSC) derived from human dental pulp has shown promising results in animal models, but still with mechanisms and consequences that are not entirely clear. The study aims to evaluate the effects of intravenous MSC on rats with IS regarding neurological function and histological areas of ischemia. Thirty-two male Wistar rats underwent temporary occlusion of the middle cerebral artery (TOMCA) for 60 minutes and were divided into two groups of 16 animals each. One group received dental pulp MSC intravenously, and another received saline 2 hours after TOMCA. The animals were then evaluated using the neurological functionality scales for 15 days, and at the end of the experiment period, the histological areas of cerebral ischemia were analysed. All animals presented ischemic areas and neurological deficits compatible with IS. There was partial recovery of the functionality scores over the evaluation period, and all animals presented focal cerebral ischemia measured by histological analysis; however, there was no statistical difference between the groups. The TOMCA model was effective in reproducing IS. Although we found no difference between treatment groups, our results were useful in showing the pattern of neurological recovery presented by animals treated with dental pulp MSC and the need to extend the evaluation time for a longer period and use more sensitive functional tests. The results add valuable data for improving research with dental pulp MSC in the murine model of IS.

Human umbilical cord blood-derived mesenchymal stem cells therapy for cerebral infarction in animal model: A meta-analysis

Aim: Cerebral infarction (CI) is a serious cerebrovascular infarction disease. In recent years, the use of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) has received attention as a new alternative for treating CI in animal model. This systematic review evaluated the efficacy and safety of hUCB-MSCs, using as a treatment in improving functional recovery of CI in animal model. Methods: Electronic databases through July 5, 2023 were searched to identify relevant studies that controlled hUCB-MSCs treatment studies focusing on CI in animal model. We independently selected and assessed the relevant studies. Results: 27 studies that fulfilled the inclusion criteria were included. Compared with control group, significant beneficial effects were observed in hUCB-MSCs group regarding the neurological deficit scores (mean difference [MD]: −1.57, 95% confidential interval [CI]: −2.06, −1.08, P<0.00001), infarct size (MD: −2.82, 95% CI: −4.14, −1.49, P<0.0001).

Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study

Aging is accompanied by deterioration in physical condition, and creates high risks of diseases. Stem cell therapy exhibited promising potential in delaying aging. However, the unelucidated therapeutic mechanism limits future clinical application. Herein, to systematically understand the response to stem cell transfusion at the molecular level, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cell (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC in delaying aging.

PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSC-mediated alleviation of decompensated liver cirrhosis in rats

BackgroundDecompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathies. Human umbilical cord mesenchymal stem cell (hUCMSC) therapy has emerged as a novel treatment alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not entirely understood.MethodsWe constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and CCL4. Performing dynamic detection of liver morphology and function in rats for 11 weeks, various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were thoroughly investigated, according to ascites examination, histopathological, and related blood biochemical analyses. Flow cytometry analysis of rat liver, immunofluorescence, and RT-qPCR was performed to examine the changes in the liver immune microenvironment after hucMSCs treatment. We performed RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro to explore possible signaling pathways. PPARγ antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre-exhaustion of macrophages in DLC rats’ livers, respectively.ResultsWe found that changing the two key issues, the frequency and initial phase of hUCMSCs infusion, can affect the efficacy of hUCMSCs, and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type by activating the PPARγ signaling pathway in the liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPARγ activation with GW9662 and pre-exhaustion of macrophages in DLC rats’ liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats.ConclusionsThese data demonstrated that the optimal hUCMSCs treatment effectively inhibits the ascites formation, prolongs survival and significantly improves liver structure and function in DLC rats through the activation of the PPARγ signaling pathway within liver macrophages. Our study compared the efficacy of different hUCMSCs infusion regimens for DLC, providing new insights on cell-based therapies for regenerative medicine.

Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI)

BackgroundCritical limb ischemia (CLI) is associated with increased risk of tissue loss, leading to significant morbidity and mortality. Therapeutic angiogenesis using cell-based treatments, notably mesenchymal stem cells (MSCs), is essential for enhancing blood flow to ischemic areas in subjects suffering from CLI. The objective of this study was to evaluate the feasibility of using placenta-derived mesenchymal stem cells (P-MSCs) in patients with CLI.MethodsThis phase I dose-escalation study investigated P-MSCs in nine CLI patients who were enrolled into each of the two dosage groups (20 × 106 and 60 × 106 cells), delivered intramuscularly twice, two months apart. The incidence of treatment-related adverse events was the primary endpoint. The decrease in inflammatory cytokines, improvement in the ankle-brachial pressure index (ABI), maximum walking distance, vascular collateralization, alleviation of rest pain, healing of ulceration, and avoidance of major amputation in the target leg were the efficacy outcomes.ResultsAll dosages of P-MSCs, including the highest tested dose of 60 × 106 cells, were well tolerated. During the 6-month follow-up period, there was a statistically significant decrease in IL-1 and IFN-γ serum levels following P-MSC treatment. The blood lymphocyte profile of participants with CLI did not significantly differ, suggesting that the injection of allogeneic cells did not cause T-cell proliferation in vivo. We found clinically substantial improvement in rest pain, ulcer healing, and maximum walking distance after P-MSC implantation. In patients with CLI, we performed minor amputations rather than major amputations. Angiography was unable to demonstrate new small vessels formation significantly.ConclusionThe observations from this phase I clinical study indicate that intramuscular administration of P-MSCs is considered safe and well tolerated and may dramatically improve physical performance and minimize inflammatory conditions in patients with CLI.Trial registration: IRCT, IRCT20210221050446N1. Registered May 09, 2021.

HucMSCs treatment prevents pulmonary fibrosis by reducing circANKRD42-YAP1-mediated mechanical stiffness.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown cause. The most typical characteristic of IPF is gradual weakening of pulmonary elasticity and increase in hardness/rigidity with aging. This study aims to identify a novel treatment approach for IPF and explore mechanism of mechanical stiffness underlying human umbilical cord mesenchymal stem cells (hucMSCs) therapy. Target ability of hucMSCs was examined by labeling with cell membrane dye Dil. Anti-pulmonary fibrosis effect of hucMSCs therapy by reducing mechanical stiffness was evaluated by lung function analysis and MicroCT imaging system and atomic force microscope in vivo and in vitro. Results showed that stiff environment of fibrogenesis caused cells to establish a mechanical connection between cytoplasm and nucleus, initiating expression of related mechanical genes such as Myo1c and F-actin. HucMSCs treatment blocked force transmission and reduced mechanical force. For further exploration of mechanism, ATGGAG was mutated to CTTGCG (the binding site of miR-136-5p) in the full-length sequence of circANKRD42. Wildtype and mutant plasmids of circANKRD42 were packaged into adenovirus vectors and sprayed into lungs of mice. Mechanistic dissection revealed that hucMSCs treatment repressed circANKRD42 reverse splicing biogenesis by inhibiting hnRNP L, which in turn promoted miR-136-5p binds to 3'-Untranslated Region (3'-UTR) of YAP1 mRNA directly, thus inhibiting translation of YAP1 and reducing YAP1 protein entering nucleus. The condition repressed expression of related mechanical genes to block force transmission and reduce mechanical forces. The mechanosensing mechanism mediated directly by circANKRD42-YAP1 axis in hucMSCs treatment, which has potential general applicability in IPF treatment.

O-Vanillin Modulates Cell Phenotype and Extracellular Vesicles of Human Mesenchymal Stem Cells and Intervertebral Disc Cells.

Human mesenchymal stem cell (hMSC) and extracellular vesicle (EV) therapy is a promising treatment for discogenic low back pain (LBP). Although promising, major obstacles remain to be overcome. Cellular senescence reduces self-renewal and multipotent potentials, and the senescence-associated secretory phenotype creates an inflammatory environment negatively affecting tissue homeostasis. Reducing senescence could therefore improve regenerative approaches. Ortho-Vanillin (o-Vanillin) has senolytic activity and anti-inflammatory properties and could be a valuable supplement to MSC and EV therapy. Here, we used direct co-culture experiments to evaluate proteoglycan synthesis, inflammatory mediators, and senescent cells in the presence or absence of o-Vanillin. EV release and transfer between hMSCs and intervertebral disc cells (DCs) was examined, and the effect on hMSC differentiation and DC phenotype was evaluated in the presence and absence of o-Vanillin. This study demonstrates that o-Vanillin affects cell communication, enhances hMSC differentiation and improves DC phenotype. Co-cultures of DCs and hMSCs resulted in increased proteoglycan synthesis, a decreased number of senescent cells and decreased release of the cytokines IL6 and 8. Effects that were further enhanced by o-Vanillin. o-Vanillin profoundly increased EV release and/or uptake by hMSCs and DCs. DC markers were significantly upregulated in both cell types in response to conditioned media of o-Vanillin treated donor cells. Collectively, this study demonstrates that o-Vanillin affects hMSC and DC crosstalk and suggests that combining hMSCs and senolytic compounds may improve the outcome of cell supplementation and EV therapy for LBP.

Attenuation of experimental osteoarthritis with human adipose-derived mesenchymal stem cell therapy: inhibition of the pyroptosis in chondrocytes.

To explore the role and mechanism of human adipose-derived mesenchymal stem cells (hAD-MSCs) in the treatment of osteoarthritis (OA). OA hulth model of Sprague Dawley (SD) rats and 20ng/ml TNF-α treated chondrocytes were used as models of OA in vivo and in vitro, respectively. hAD-MSCs were administrated in the articular cavity by injection in vivo and co-cultured with chondrocytes using transwell in vitro. Haematoxylin and eosin staining and Safranin-O/Fast green staining were performed to detect tissue destruction and histopathology. Scanning electron microscopy and transmission electron microscopy were used to observe the ultrastructure of chondrocytes. The pyroptosis signaling pathway-related proteins were detected by immunohistochemistry, immunofluorescence, qRT-PCR and Western blot. And small interference technology was used to study the mechanism in depth. hAD-MSCs could delay the development of rat OA, improve the pathological changes of joints, inhibit the expression of NLRP3, Caspase1, GSDMD and TNFR1. In vitro, the expression of pyroptosis signal proteins in chondrocytes was significantly elevated when stimulated with TNF-α, the level of inflammatory factors such as IL-1β, IL-18 was increased, and the cell morphology was significantly destroyed. While co-cultured with hAD-MSCs, these syndromes were reversed. Knockout of TNFR1 also returned the upregulation of pyroptosis signals which caused by TNF-α. These results demonstrated that hAD-MSCs could inhibit pyroptosis signaling pathway of chondrocytes induced by TNF-α, which have raised our understanding of the role of hAD-MSCs as promising therapy for the management of OA.

HUMSC vs. hUMSC-Exosome: Which One Is Better for Epilepsy?

Epilepsy is a disorder characterized by abnormal brain cell activity that results in seizures. It causes progressive damage to neurons. Epilepsy treatment currently focuses mostly on symptoms, which also have risks of unwanted side effects. There is currently no effective treatment to prevent epileptogenesis and the resulting neural damage. Human Umbilical Cord Mesenchymal Stem Cell (hUMSC) and exosome therapy are examples of cellular therapies that may be used to treat degenerative diseases, such as epilepsy, or cell damage. However, there is still little research on the use of hUMSCs or hUMSC–exosomes for treating epilepsy. Hence, the purpose of this paper is to compare the potential and risk of hUMSCs and hUMSC–exosomes as therapies for epilepsy. This article provides a brief summary of hUMSCs and hUMSC–exosomes in multiple aspects, such as the isolation and purification method, the mechanism of action, immunological compatibility, tumorigenicity, the risk of transmitting disease, stability upon storage, the potential of new composition with other substances, and also ethical and political issues. We conclude that hUMSCs and hUMSC–exosomes have therapeutic potential for epilepsy, with hUMSC–exosomes being safer due to their reduced immunogenicity.

Abstract P1133: Association Of Mesenchymal Stem Cells Therapy And An Agonist Of Adenosine Receptor On Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an intense inflammatory component leading to vascular remodeling, increasing the pulmonary artery pressure, eventually resulting in right ventricular dysfunction. Hypothesis: Association of human mesenchymal stem cells (hMSC) therapy and LASSBio-1860 (agonist of adenosine receptors) would reduce the inflammatory response and vascular remodeling, decreasing the vascular resistance and pulmonary artery pressure, improving right ventricle function and reducing hypertrophy. Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. PAH was induced in male Wistar rats by injection of monocrotaline (MCT; 60 mg/kg, i.p.) and confirmed within 14 days by transthoracic echocardiography. Groups were orally treated daily during 14 days with vehicle, LASSBio-1860 (180 μmol/kg) after a single intravenous injection of 10 5 hMSC At the end of protocol, tissues were collected and processed to evaluate expression of proteins using immunohistochemical and western-blotting analysis. Results: Mean pulmonary artery acceleration time (PAAT) was reduced in MCT-induced PAH group compared to the control group from 31.0 ± 1.5 to 21.9 ± 1.3 ms. In contrast, the association of LASSBio-1860 and hMSC has recovered the PAAT to 31.0 ± 2.0 ms, which effect was not observed in isolated treatment either with LASSBio-1860 or hMSC (23.5 ± 2.1 and 22.2 ± 2.2 ms). Table 1 shows hemodynamic, molecular and immunohistochemical parameters. In conclusion, the association of LASSBio-1860 and hMSC improved hemodynamic, morphologic and inflammatory parameters in an MCT-induced model of PAH.

Intrarenal arterial administration of human umbilical cord-derived mesenchymal stem cells effectively preserved the residual renal function of diabetic kidney disease in rat

BackgroundThis experimental study was designed as a preclinical study for testing the hypothesis that intrarenal arterial (IRA) transfusion of human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) therapy preserved the residual renal function of diabetic kidney disease (DKD) in rat [induction by 5/6 nephrectomy of left kidney and right nephrectomy, followed by intraperitoneal administration of aminoguanidine (180 mg/kg) and streptozotocin (30 mg/kg)].MethodsAnimals (n = 24) were categorized into group 1 (sham-operated control), group 2 (DKD), group 3 [DKD + HUCDMSCs (2.1 × 105/IRA injection at day 28 after CKD induction)] and group 4 [(DKD + HUCDMSCs (6.3 × 105/IRA injection)].ResultsBy day 60 after DKD induction, the kidneys were harvested and the result showed that the creatinine level, ratio of urine protein/urine creatinine and kidney injury score were lowest in group 1, highest in group 2 and significantly lower in group 4 than in group 3 (all p < 0.0001). The protein expressions of apoptotic (cleaved caspase-3/cleaved PARP/mitochondrial Bax), fibrotic (TGF-ß/p-Smad3), autophagic (ratio of LC3B-II/LC3B-I, Atg5/Beclin-1), oxidative stress (NOX-1/NOX-2/oxidized protein/p22phox), mitochondrial/DNA-damaged (cytosolic-cytochrome-C/DRP1/γ-H2AX) and inflammatory (MMP-9/TNF-α/p-NF-κB) biomarkers exhibited an identical pattern, whereas the protein expressions of angiogenesis factors (CD31/vWF/vascularity) exhibited an opposite pattern of creatinine level among the groups (all p < 0.0001). Histopathological findings demonstrated the renal tubular-damaged (KIM-1)/kidney fibrosis area/oxidative stress (8-OHdG + cells) expressed an identical pattern, whereas the podocyte components (ZO-1/synaptopodin/podocin) exhibited an opposite pattern of creatinine level among the groups (all p < 0.0001). No tumorigenesis or immune rejection event was identified.ConclusionIRA injection of xenogeneic MSCs was safe and effectively protected the residual renal function and architectural integrity in DKD rat.

HucMSCs-exosomes containing miR-21 promoted estrogen production in ovarian granulosa cells via LATS1-mediated phosphorylation of LOXL2 and YAP

BackgroundPremature ovarian failure (POF) is one of the common disorders found in women leading to 1% female infertility. Clinical features of POF are hypoestrogenism or estrogen deficiency. With the development of regenerative medicine, human mesenchymal stem cells (hMSCs) therapy brings new prospects for POF. This research aims to reveal the therapeutic effects and potential mechanisms of human umbilical cord mesenchymal stem cells (hucMSCs)-derived exosomes on POF. MethodsThe mRNA and protein expressions in hucMSCs and ovarian granulosa cells (KGN and SVOG cells) were assessed using qRT-PCR and western blot. ELISA assay was performed to evaluate estradiol (E2) secretion in granulosa cells. The binding relationship between miR-21 and LATS1 was verified by dual-luciferase reporter assay and RNA binding protein immunoprecipitation assay (RIP) assay. Additionally, Immunoprecipitation assay was carried out to confirm Lysyl oxidase like 2 (LOXL2) was phosphorylated by large tumor suppressor 1 (LATS1). Finally, the binding relationships between Yes-associated protein (YAP), StAR and LOXL2 were verified by dual-luciferase reporter assay and/or chromatin immunoprecipitation assay (ChIP) assay. ResultsHere our results displayed that miR-21 was overexpressed in hucMSCs and hucMSCs-derived exosomes, compared with that ovarian granulosa cells. hucMSC-exo with overexpressing miR-21 could markedly promote the secretion of estrogen in ovarian granulosa cells. LATS1 overexpression in ovarian granulosa cells reduced the secretion of estrogen. We subsequently confirmed that LATS1 was the target of miR-21. In addition, LATS1 could regulate StAR expression by phosphorylating LOXL2 and YAP. ConclusionmiR-21 carried by hucMSCs-derived exosomes could downregulate LATS1, thereby reducing phosphorylated LOXL2 and YAP, and ultimately promoting estrogen secretion in ovarian granulosa cells.

Mesenchymal Stem Cell Behavior on Soft Hydrogels with Aligned Surface Topographies.

Human mesenchymal stem cells (HMSCs) are important for cell-based therapies. However, the success of HMSC therapy requires large-scale in vitro expansion of these multipotent cells. The traditional expansion of HMSCs on tissue-culture-treated stiff polystyrene induces significant changes in their shape, multipotency, and secretome, leading to early senescence and subdued paracrine activity. To enhance their therapeutic potential, here, we have developed two-dimensional soft hydrogels with imprinted microscale aligned grooves for use as HMSC culture substrates. We showed that, depending on the dimensions of the topographical features, these substrates led to lower cellular spreading and cytoskeletal tension, maintaining multipotency and osteogenic and adipogenic differentiate potential, while lowering cellular senescence. We also observed a greater capacity of HMSCs to produce anti-inflammatory cytokines after short-term priming on these hydrogel substrates. Overall, these soft hydrogels with unique surface topography have shown great promise as in vitro culture substrates to maximize the therapeutic potential of HMSCs.

Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy.

No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance.

Metabolic Rewiring by Human Placenta-Derived Mesenchymal Stem Cell Therapy Promotes Rejuvenation in Aged Female Rats.

Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced responses at the metabolite and protein levels and serum biomarker(s) of aging and/or rejuvenation. We observed weight loss after hPD-MSC therapy. Importantly, insulin-like growth factor-I (IGF-I), known prolongs healthy life spans, were markedly elevated in serum. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis identified 176 metabolites, among which the levels of 3-hydroxybutyric acid, glycocholic acid, and taurine, which are associated with health and longevity, were enhanced after hPD-MSC stimulation. Furthermore, after hPD-MSC therapy, the levels of vitamin B6 and its metabolite pyridoxal 5′-phosphate were markedly increased in the serum and liver, respectively. Interestingly, hPD-MSC therapy promoted serotonin production due to increased vitamin B6 metabolism rates. Increased liver serotonin levels after multiple-injection therapy altered the expression of mRNAs and proteins associated with hepatocyte proliferation and mitochondrial biogenesis. Changes in metabolites in circulation after hPD-MSC therapy can be used to identify biomarker(s) of aging and/or rejuvenation. In addition, serotonin is a valuable therapeutic target for reversing aging-associated liver degeneration.

Neuroprotection and gliosis attenuation by intravenous application of human mesenchymal stem cells (hMSC) following ventral root crush in mice

Rupture and stretching of spinal roots are common incidents that take place in high-energy accidents. The proximal axotomy of motoneurons by crushing of ventral roots is directly related to the degeneration of half of the lesioned population within the first two weeks. Moreover, only a small percentage of surviving motoneurons can successfully achieve regeneration after such a proximal lesion, and new treatments are necessary to improve this scenario. In this sense, mesenchymal stem cells (MSC) are of great interest once they secrete a broad spectrum of bioactive molecules that are immunomodulatory and can restore the environment after a lesion. The present work aimed at studying the effects of human mesenchymal stem cells (hMSC) therapy after ventral root crush (VRC) in mice. We evaluated motoneuron survival, glial reaction, and synapse preservation at the ventral horn. For this purpose, C57BL/6 J were submitted to a crush procedure of L4 to L6 ventral roots and treated with a single intravenous injection of adipose-derived hMSC. Evaluation of the results was carried out at 7, 14, and 28 days after injury. Analysis of motoneuron survival and astrogliosis showed that hMSC treatment resulted in higher motoneuron preservation (motoneuron survival ipsi/contralateral ratio: VRC group = 53%, VRC + hMSC group = 66%; p < 0.01), combined with reduction of astrogliosis (ipsi/contralateral GFAP immunolabeling: VRC group = 470%, VRC + hMSC group = 250%; p < 0.001). The morphological classification and Sholl analysis of microglial activation revealed that hMSC treatment reduced type V and increased type II profiles, indicating an enhancement of surveying over activated microglial cells. The glial reactivity modulation directly influenced synaptic inputs in apposition to axotomized motoneurons. In the hMSC-treated group, synaptic maintenance was increased (ipsi/contralateral synaptophysin immunolabeling: VRC group = 53%, VRC + hMSC group = 64%; p < 0.05). Overall, the present data show that intravenous injection of hMSC has neuroprotective and anti-inflammatory effects, decreasing reactive astrogliosis, and microglial reaction. Also, such cell therapy results in motoneuron preservation, combined with significant maintenance of spinal cord circuits, in particular those related to the ventral horn.

Clinical Efficacy and Safety of Human Mesenchymal Stem Cell Therapy for Degenerative Disc Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Degenerative disc disease (DDD) can cause severe low back pain, which will have a serious negative impact on the ability to perform daily tasks or activities. For the past few years, mesenchymal stem cell (MSC) transplantation has emerged as a promising strategy for the treatment of DDD. However, the clinical efficacy of MSC in the treatment of DDD still lacks clinical evidence and is controversial. We conducted a meta-analysis with randomized controlled trials (RCTs) to evaluate the clinical efficacy and safety of MSC transplantation in patients with DDD. We searched major databases using terms from the database's inception through March 2021. The Cochrane bias risk assessment tool was used to assess quality. The analysis showed that MSC therapy could decrease visual analog scale (VAS) scores (SMD = −0.50, 95%CI = −0.68 ~ −0.33, P < 0.00001) and Oswestry Disability Index (ODI) scores (SMD = −0.27, 95%CI = −0.44 ~ −0.09, P = 0.003). The outcomes with subgroup analysis showed that MSC therapy could decrease VAS scores in 3 months (P = 0.001), 6 months (P = 0.01), 12 months (P = 0.02), and ≥24 months (P = 0.002) and ODI scores in ≥24 months (P = 0.006). Pooled analysis showed that MSC therapy has a higher ratio of patients at most thresholds but particularly at the MIC (minimally important change) (P = 0.0002) and CSC (clinically significant change) (P = 0.0002) in VAS and MIC (P = 0.0005) and CSC (P = 0.001) pain responders in ODI. Adverse events (AE) of treatment-emergent adverse events (TEAE), back pain, arthralgia, and muscle spasms were not statistically significant between the two groups. However, our further statistical analysis showed that MSC therapy may induce AE of TEAE related to study treatment (OR = 3.05, 95%CI = 1.11 ~ 8.40, P = 0.03). In conclusion, this study pooled the main outcomes and showed that MSC therapy could significantly decrease VAS and ODI scores in patients with DDD. Distinctly, the findings of this meta-analysis suggest a novel therapeutic strategy for patients with chronic low back pain (LBP) and lumbar dysfunction by DDD.