PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25+ T Cells in Acute Myocardial Infarction Rat Model.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25+ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.

Mesenchymal stem cell therapy on top of triple therapy with remdesivir, dexamethasone, and tocilizumab improves PaO2/FiO2 in severe COVID-19 pneumonia.

Background: Despite patients with severe coronavirus disease (COVID-19) receiving standard triple therapy, including steroids, antiviral agents, and anticytokine therapy, health condition of certain patients continue to deteriorate. In Taiwan, the COVID-19 mortality has been high since the emergence of previous variants of this disease (such as alpha, beta, or delta). We aimed to evaluate whether adjunctive infusion of human umbilical cord mesenchymal stem cells (MSCs) (hUC-MSCs) on top of dexamethasone, remdesivir, and tocilizumab improves pulmonary oxygenation and suppresses inflammatory cytokines in patients with severe COVID-19. Methods: Hospitalized patients with severe or critical COVID-19 pneumonia under standard triple therapy were separated into adjuvant hUC-MSC and non-hUC-MSC groups to compare the changes in the arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio and biological variables. Results: Four out of eight patients with severe or critical COVID-19 received either one (n = 2) or two (n = 2) doses of intravenous infusions of hUC-MSCs using a uniform cell dose of 1.0 × 108. Both high-sensitivity C-reactive protein (hs-CRP) level and monocyte distribution width (MDW) were significantly reduced, with a reduction in the levels of interleukin (IL)-6, IL-13, IL-12p70 and vascular endothelial growth factor following hUC-MSC transplantation. The PaO2/FiO2 ratio increased from 83.68 (64.34-126.75) to 227.50 (185.25-237.50) and then 349.56 (293.03-367.92) within 7 days after hUC-MSC infusion (P < 0.001), while the change of PaO2/FiO2 ratio was insignificant in non-hUC-MSC patients (admission day: 165.00 [102.50-237.61]; day 3: 100.00 [72.00-232.68]; day 7: 250.00 [71.00-251.43], P = 0.923). Conclusion: Transplantation of hUC-MSCs as adjunctive therapy improves pulmonary oxygenation in patients with severe or critical COVID-19. The beneficial effects of hUC-MSCs were presumably mediated by the mitigation of inflammatory cytokines, characterized by the reduction in both hs-CRP and MDW.

Human Olfactory Ensheathing Cell Transplantation Improves Motor Function in a Mouse Model of Type 3 Spinocerebellar Ataxia.

Spinocerebellar ataxia (SCA) is a progressive neurodegenerative disease that affects the cerebellum and spinal cord. Among the 40 types of SCA, SCA type 3 (SCA3), also referred to as Machado-Joseph disease, is the most common. In the present study, we investigated the therapeutic effects of intracranial transplantation of human olfactory ensheathing cells (hOECs) in the ATXN3-84Q mouse model of SCA3. Motor function begins to decline in ATXN3-84Q transgenic mice at approximately 13 weeks of age. ATXN3-84Q mice that received intracranial hOEC transplantation into the dorsal raphe nucleus of the brain exhibited significant improvements in motor function, as measured by the rotarod performance test and footprint pattern analysis. In addition, intracranial hOEC transplantation alleviated cerebellar inflammation, prohibited Purkinje cells from dying, and enhanced the neuroplasticity of cerebellar Purkinje cells. The protein levels of tryptophan hydroxylase 2, the rate-limiting enzyme for serotonin synthesis in the cerebellum, and ryanodine receptor (RYR) increased in mice that received intracranial hOEC transplantation. Because both serotonin and RYR can enhance Purkinje cell maturation, these effects may account for the therapeutic benefits mediated by intracranial hOEC transplantation in SCA3 mice. These results indicate that intracranial hOEC transplantation has potential value as a novel strategy for treating SCA3.