BACKGROUND: The effects of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment on coronavirus disease 2019 (COVID-19) patients have been preliminarily characterized. However, real-world data on the safety and efficacy of intravenous transfusions of MSCs in hospitalized COVID-19 patients at the convalescent stage remain to be reported. METHODS: This was a single-arm, multicenter, real-word study in which a contemporaneous external control was included as the control group. Besides, severe and critical COVID-19 patients were considered together as the severe group, given the small number of critical patients. For a total of 110 patients, 21 moderate patients and 31 severe patients were enrolled in the MSC treatment group, while 26 moderate patients and 32 severe patients were enrolled in the control group. All patients received standard treatment. The MSC treatment patients additionally received intravenous infusions of MSCs at a dose of 4 × 10 7 cells on days 0, 3, and 6, respectively. The clinical outcomes, including adverse events (AEs), lung lesion proportion on chest computed tomography, pulmonary function, 6-min walking distance (6-MWD), clinical symptoms, and laboratory parameters, were measured on days 28, 90, 180, 270, and 360 during the follow-up visits. RESULTS: In patients with moderate COVID-19, MSC treatment improved pulmonary function parameters, including forced expiratory volume in the first second (FEV1) and maximum forced vital capacity (VCmax) on days 28 (FEV1, 2.75 [2.35, 3.23] vs . 2.11 [1.96, 2.35], P  = 0.008; VCmax, 2.92 [2.55, 3.60] vs . 2.47 [2.18, 2.68], P  = 0.041), 90 (FEV1, 2.93 [2.63, 3.27] vs . 2.38 [2.24, 2.63], P  = 0.017; VCmax, 3.52 [3.02, 3.80] vs . 2.59 [2.45, 3.15], P  = 0.017), and 360 (FEV1, 2.91 [2.75, 3.18] vs . 2.30 [2.16, 2.70], P  = 0.019; VCmax,3.61 [3.35, 3.97] vs . 2.69 [2.56, 3.23], P  = 0.036) compared with the controls. In addition, in severe patients, MSC treatment notably reduced the proportion of ground-glass lesions in the whole lung volume on day 90 ( P  = 0.045) compared with the controls. No difference in the incidence of AEs was observed between the two groups. Similarly, no significant differences were found in the 6-MWD, D-dimer levels, or interleukin-6 concentrations between the MSC and control groups. CONCLUSIONS: Our results demonstrate the safety and potential of MSC treatment for improved lung lesions and pulmonary function in convalescent COVID-19 patients. However, comprehensive and long-term studies are required to confirm the efficacy of MSC treatment. TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR2000031430.
Humans ; COVID-19/therapy* ; Female ; Male ; Mesenchymal Stem Cell Transplantation/adverse effects* ; Middle Aged ; Adult ; Umbilical Cord/cytology* ; Mesenchymal Stem Cells/cytology* ; SARS-CoV-2 ; Aged ; Treatment Outcome

Pulmonary diseases, as a prevalent category of respiratory system disorders, have become a significant global public health concern. The increasing incidence of these diseases, caused by environmental pollution and occupational hazards, poses a substantial threat to human health and the overall quality of life. Mesenchymal stem cells (MSCs) are known for their remarkable immunomodulatory, anti-bacterial, and anti-apoptotic capabilities. Exosomes derived from MSCs, carrying a diverse array of proteins, lipids, nucleic acids, and other bio-active molecules, have demonstrated considerable therapeutic potential in treating pulmonary diseases, and have come to the forefront of medical research. This review summarized the therapeutic role of exosomes derived from various sources of mesenchymal stem cells in the context of pulmonary diseases, aiming to provide a robust foundation for their clinical application in diagnosis and treatment.
Exosomes/transplantation* ; Humans ; Mesenchymal Stem Cells/metabolism* ; Lung Diseases/therapy* ; Animals

Objective To investigate the effects and underlying mechanisms of human placental chorionic plate-derived mesenchymal stem cells (hpcMSCs) on cognitive dysfunction, neuroinflammation, neuronal damage and synaptic plasticity in a mouse model of stroke. Methods A mouse model of middle cerebral artery occlusion (MCAO) was adopted. The mice were randomly divided into three groups: sham operation group, MCAO group and hpcMSCs treatment group, with seven mice in each group. The hpcMSCs treatment group received hpcMSCs transplantation on the 1st, 3rd and 10th day after MCAO. One month after MCAO, the cognitive ability of the mice was evaluated by Morris water maze and Y maze behavioral tests; the morphological changes and synaptic functions of hippocampal neurons were analyzed by HE staining, Nissl staining, Golgi staining and immunofluorescence staining techniques; the density and activation status of microglia was analyzed by Fluorescent labeling method; the levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in brain tissue were analyzed by ELISA; the expressions of phosphorylated-mitogen-activated protein kinase kinase 1 (p-MEK1), phosphorylated-extracellular regulated protein kinase (p-ERK) and phosphorylated-cAMP-response element binding protein (p-CREB) and other proteins related to neuroprotection in the signal pathways were detected by Western blotting; and electrophysiological detection was performed using hippocampal slices in vitro. Results Compared with the MCAO group, mice in the hpcMSCs treatment group showed significant improvements, including improved cognitive ability, alleviated neuroinflammation (demonstrated by reduced microglial activation and decreased levels of inflammatory factors TNF-α, IL-1β and IL-6), and increased neuronal density with normalized morphology of neurons in the hippocampal CA1 region. The treatment group also demonstrated a significantly increased number of Nissl-positive cells and density of dendritic spines of hippocampal neurons, along with restored frequency of miniature excitatory postsynaptic potential (mEPSP). Moreover, hpcMSCs treatment significantly increased the expression levels of p-MEK1, p-ERK and p-CREB in the hippocampus. Conclusion Transplantation of hpcMSCs ameliorates cognitive dysfunction and hippocampal neuronal injury in stroke mice through the reduction of neuroinflammation, restoration of hippocampal neuronal function, promotion of synaptic plasticity and activation of the MEK/ERK/CREB signaling pathway. These findings suggest a new potential therapeutic approach for post-stroke neural repair.
Animals ; Hippocampus/physiopathology* ; Mice ; Cognitive Dysfunction/etiology* ; Mesenchymal Stem Cell Transplantation ; Male ; Neurons/metabolism* ; Stroke/metabolism* ; Humans ; Neuroinflammatory Diseases/therapy* ; Female ; Cyclic AMP Response Element-Binding Protein/metabolism* ; Disease Models, Animal ; Mesenchymal Stem Cells/cytology* ; Mice, Inbred C57BL

Stem cell treatment may enhance erectile dysfunction (ED) in individuals with cavernous nerve injury (CNI). Nevertheless, no investigations have directly ascertained the implications of varying amounts of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) on ED. We compare the efficacy of three various doses of HUC-MSCs as a therapeutic strategy for ED. Sprague-Dawley rats (total = 175) were randomly allocated into five groups. A total of 35 rats underwent sham surgery and 140 rats endured bilateral CNI and were treated with vehicles or doses of HUC-MSCs (1 × 10 6 cells, 5 × 10 6 cells, and 1 × 10 7 cells in 0.1 ml, respectively). Penile tissues were harvested for histological analysis on 1 day, 3 days, 7 days, 14 days, 28 days, 60 days, and 90 days postsurgery. It was found that varying dosages of HUC-MSCs enhanced the erectile function of rats with bilateral CNI and ED. Moreover, there was no significant disparity in the effectiveness of various dosages of HUC-MSCs. However, the expression of endothelial markers (rat endothelial cell antigen-1 [RECA-1] and endothelial nitric oxide synthase [eNOS]), smooth muscle markers (alpha smooth muscle actin [α-SMA] and desmin), and neural markers (neurofilament [RECA-1] and neurogenic nitric oxide synthase [nNOS]) increased significantly with prolonged treatment time. Masson's staining demonstrated an increased in the smooth muscle cell (SMC)/collagen ratio. Significant changes were detected in the microstructures of various types of cells. In vivo imaging system (IVIS) analysis showed that at the 1 st day, the HUC-MSCs implanted moved to the site of damage. Additionally, the oxidative stress levels were dramatically reduced in the penises of rats administered with HUC-MSCs.
Male ; Animals ; Erectile Dysfunction/metabolism* ; Rats, Sprague-Dawley ; Mesenchymal Stem Cell Transplantation/methods* ; Rats ; Penis/pathology* ; Humans ; Disease Models, Animal ; Umbilical Cord/cytology* ; Peripheral Nerve Injuries/complications* ; Mesenchymal Stem Cells ; Nitric Oxide Synthase Type III/metabolism* ; Actins/metabolism* ; Nitric Oxide Synthase Type I/metabolism*

OBJECTIVES: To investigate whether human umbilical cord mesenchymal stem cells (HUC-MSCs) play protective effects against white matter injury (WMI) in neonatal rats via activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase-1 (HO-1) signaling pathway. METHODS: A neonatal WMI model was established in 3-day-old Sprague-Dawley rats by unilateral common carotid artery ligation combined with hypoxia. The study comprised two parts. (1) Rats were randomized into sham, hypoxia-ischemia (HI), and HUC-MSC groups (n=36 per group); brain tissues were collected at 7, 14, and 21 days after modeling. (2) Rats were randomized into sham, HI, HUC-MSC, and HUC-MSC+ML385 (Nrf2 inhibitor) groups (n=12 per group); tissues were collected 14 days after modeling. Hematoxylin-eosin staining assessed histopathology, and Luxol fast blue staining evaluated myelination. Immunohistochemistry examined the localization and expression of Nrf2, myelin basic protein (MBP), and proteolipid protein (PLP). Immunofluorescence assessed synaptophysin (SYP) and postsynaptic density-95 (PSD-95). Western blotting quantified Nrf2, Keap1, HO-1, SYP, PSD-95, MBP, and PLP. Spatial learning and memory were evaluated by the Morris water maze. RESULTS: At 7, 14, and 21 days after modeling, the sham group showed intact white matter, whereas the HI group exhibited white matter disruption, cellular vacuolation, and disorganized nerve fibers. These pathological changes were attenuated in the HUC-MSC group. Compared with the HI group, the HUC-MSC group showed increased Nrf2 immunopositivity and protein levels, increased HO-1 protein levels, and decreased Keap1 protein levels (P<0.05). Compared with the HI group, the HUC-MSC group had higher SYP and PSD-95 immunofluorescence intensities and protein levels, higher MBP and PLP positivity and protein levels, increased mean optical density of myelin, more platform crossings, and longer time in the target quadrant (all P<0.05). These improvements were reduced in the HUC-MSC+ML385 group compared with the HUC-MSC group (P<0.05). CONCLUSIONS HUC-MSCs may promote oligodendrocyte maturation and synaptogenesis after neonatal WMI by activating the Nrf2/Keap1/HO-1 pathway, thereby improving spatial cognitive function.
NF-E2-Related Factor 2/physiology* ; Animals ; Rats, Sprague-Dawley ; Signal Transduction/physiology* ; Humans ; Rats ; White Matter/pathology* ; Kelch-Like ECH-Associated Protein 1/physiology* ; Umbilical Cord/cytology* ; Heme Oxygenase-1/physiology* ; Animals, Newborn ; Male ; Mesenchymal Stem Cell Transplantation ; Heme Oxygenase (Decyclizing)/physiology* ; Mesenchymal Stem Cells/physiology* ; Female ; Hypoxia-Ischemia, Brain

OBJECTIVE: To analyze the effect of COVID-19 infection on the mobilization and collection of autologous peripheral blood stem cells in patients with multiple myeloma. METHODS: The general baseline data, treatment factors before mobilization collection, collection status, and treatment overview after collection of autologous peripheral blood stem cells at Beijing Chaoyang Hospital affiliated with Capital Medical University from January 1, 2020 to July 15, 2023 were analyzed. RESULTS: 269 patients underwent mobilization and collection of autologous peripheral blood stem cells. Among them, 32 cases with COVID-19 infection history (COVID-19 group) and 237 cases without COVID-19 infection history (non-COVID-19 group). In the COVID-19 group, 17 cases were treated with chemotherapy (etoposide)+G-CSF, and 15 cases were treated with plerixafor +G-CSF. In the non-COVID-19 group, 214 cases were treated with chemotherapy +G-CSF, 17 cases were treated with plerixafor +G-CSF, and 6 cases were treated with chemotherapy + plerixafor +G-CSF. The number of CD34⁺ cells, collection success rate, and excellence rate in the COVID-19 group and the non-COVID-19 group were ［5.52 (0.94-26.87) vs 4.80 (0.53-37.20)］×10⁶/kg (P =0.610), (93.8% vs 85.2%) (P =0.275), (62.5% vs 49.4%) (P =0.190), respectively. Among 113 patients mobilized with etoposide +G-CSF, the number of CD34⁺ cells, success rate, and excellence rate collected from COVID-19 infection (17 cases) and non-COVID-19 infection (96 cases) were ［7.54 (2.66-26.87) vs 7.78 (2.26-37.20)］×10⁶/kg (P =0.847), (100.0% vs 100.0%) (no P value), (82.4% vs 86.5%) (P =0.655), respectively. Among 32 patients mobilized by plerixafor +G-CSF, the number of CD34⁺ cells, success rate and excellence rate of COVID-19 infection (15 cases) and non-COVID-19 infection (17 cases) were ［3.82 (0.94-7.27) vs 4.11 (0.53-9.05)］×10⁶/kg (P =0.821), (86.7% vs 88.2%) (P =0.893), (40.0% vs 35.3%) (P =0.784), respectively. In 32 patients with COVID-19 infection, the number of CD34⁺ cells collected by etoposide +G-CSF (17 cases) and plerixafor +G-CSF (15 cases), as well as the success rate and excellence rate were ［7.54 (2.66-26.87) vs 3.82(0.94-7.27)］×10⁶/kg (P =0.004), (100.0% vs 86.7%) (P =0.120), (82.4% vs 40.0%) (P =0.014), respectively. By 2023.7.31, 232 patients (86.2%, 232/269) had received transplantation, including 24 patients in the COVID-19 group and 208 patients in the non-COVID-19 group. The median number of CD34⁺ cells infused in the two groups was ［3.67 (2.50-13.44) vs 3.11(1.12-19.89)］×10⁶/kg (P =0.058), the median days of neutrophil engraftment ［11(9-13) vs 11(9-17)］ (P =0.674), the median days of platelet engraftment ［11(0-23), 12(0-43)］ (P =0.279), respectively. CONCLUSION The history of COVID-19 infection did not affect the PBSC mobilization, collection and transplantation of patients with myeloma. In patients with COVID-19 infection, the results of chemotherapy mobilization with etoposide seems to be better than that of plerixafor mobilization, but further research is needed to clarify.
Humans ; COVID-19/complications* ; Multiple Myeloma/complications* ; Hematopoietic Stem Cell Mobilization ; Transplantation, Autologous ; Granulocyte Colony-Stimulating Factor/therapeutic use* ; Peripheral Blood Stem Cell Transplantation ; SARS-CoV-2 ; Middle Aged ; Peripheral Blood Stem Cells ; Male ; Female ; Cyclams ; Benzylamines

OBJECTIVE: To investigate the correlation between the types and quantities of immune cells in the graft and early immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their influence on clinical prognosis. METHODS: The clinical data of 83 patients with hematological diseases who received allo-HSCT in Shanxi Bethune Hospital from September 2020 to June 2023 were retrospectively analyzed. The number of mononuclear cells (MNC), CD34⁺ cells and lymphocyte subsets (including CD3⁺T, CD3⁺CD4⁺T(Th), CD3⁺CD8⁺T(Ts), NK cells and B cells) infused into the recipients was counted, and the peripheral blood lymphocytes were detected before conditioning and on days 14, 30, 60 and 100 post-HSCT. RESULTS: Multivariate analysis showed that the number of MNC in the graft affected the recovery of CD4⁺T lymphocytes after HSCT, and the number of CD4⁺T lymphocytes in the graft affected the recovery of NK cells and B cells after HSCT. The patient age, donor sex, stem cell source, degree of HLA matching, use of ATG before HSCT, the occurrence of acute graft-versus-host disease (aGVHD) after HSCT, and viral infection all affect the early cellular immune reconstitution post-HSCT. The number of infused cells had no significant impact on the median engraftment time for neutrophils and platelets after HSCT. Patients with lower numbers of CD3⁺T, CD4⁺T and B cells in the graft were more prone to viral infection after HSCT. However, the cells in the graft had no significant effect on disease recurrence or mortality. CONCLUSION The recovery rate of lymphocyte count after allo-HSCT varies. The numbers of MNC and CD4⁺T cells in the graft may be related to the cellular immune reconstitution after HSCT, while the numbers of CD34⁺,CD3⁺T,CD8⁺T,NK and B cells have no significant effect on the cellular immune reconstruction. The numbers of CD3⁺T,CD4⁺T and B cells in the graft were negatively correlated with viral infection after HSCT, but the cellular components of the graft have no obvious influence on hematopoietic reconstitution, disease recurrence, death, recurrence-free survival(RFS) and overall survival(OS) after HSCT.
Humans ; Hematopoietic Stem Cell Transplantation ; Immune Reconstitution ; Transplantation, Homologous ; Retrospective Studies ; Graft vs Host Disease/immunology* ; Male ; Female ; Killer Cells, Natural/immunology* ; Adult ; Middle Aged ; B-Lymphocytes/immunology* ; Prognosis ; Lymphocyte Subsets/immunology* ; Adolescent

OBJECTIVE: To explore the safety and efficacy of high-dose etoposide (VP-16) combined with recombinant human granulocyte colony-stimulating factor (rhG-CSF) as salvage mobilization for peripheral blood stem cells (PBSC) in newly diagnosed multiple myeloma (NDMM) patients. METHODS: From April 2021 to May 2023, eight NDMM patients who had failed to yield sufficient PBSC during initial mobilization with high-dose cyclophosphamide (CTX) combined with rhG-CSF underwent salvage mobilization with 1.2 g/m2 etoposide combined with rhG-CSF 10 μg/(kg·d). The effects and adverse reactions of initial mobilization and salvage mobilization were analyzed. RESULTS: For salvage mobilization and initial mobilization, the numbers of PBSC collections were 16 and 18, respectively. The mean value of total collected CD34⁺ cells were (11.90±5.75)×10⁶/kg and (1.67±0.75)×10⁶/kg (P =0.0010) in salvage mobilization group and initial mobilization group, respectively. The proportion of patients with a total collection of CD34⁺ cell count≥2×10⁶/kg were 100% and 37.5% (P =0.0625), and the proportion of patients with a total collection of CD34⁺ cell count≥5×10⁶/kg were 87.5% and 0% (P =0.0156) in salvage mobilization group and initial mobilization group, respectively. For five patients who underwent high-dose CTX initial mobilization but had a total CD34⁺ cell count < 2×10⁶/kg, successful collection was achieved through salvage mobilization with high-dose VP-16. Salvage mobilization with high-dose VP-16 was scheduled 2-3 weeks after failure of CTX mobilization. Adverse reactions of high-dose VP-16 mobilization did not increase compared to the initial mobilization with high-dose CTX. CONCLUSION As a salvage mobilization regimen, VP-16 1.2 g/m² combined with rhG-CSF is safe and highly effective in NDMM patients who failed to initial mobilization with high-dose CTX combined with rhG-CSF.
Humans ; Multiple Myeloma/therapy* ; Etoposide/therapeutic use* ; Hematopoietic Stem Cell Mobilization/methods* ; Cyclophosphamide/therapeutic use* ; Granulocyte Colony-Stimulating Factor ; Salvage Therapy ; Peripheral Blood Stem Cells ; Male ; Middle Aged ; Female ; Peripheral Blood Stem Cell Transplantation

OBJECTIVE: To analyze the Epstein-Barr virus (EBV) load in different lymphocyte subsets, as well as clinical characteristics and outcomes in patients with hematologic malignancies experiencing EBV reactivation. METHODS: Peripheral blood samples from patients were collected. B, T, and NK cells were isolated sorting with magnetic beads by flow cytometry. The EBV load in each subset was quantitated by real-time quantitative polymerase chain reaction (RT-qPCR). Clinical data were colleted from electronic medical records. Survival status was followed up through outpatient visits and telephone calls. Statistical analyses were performed using SPSS 25.0. RESULTS: A total of 39 patients with hematologic malignancies were included, among whom 35 patients had undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median time to EBV reactivation was 4.8 months (range: 1.7-57.1 months) after allo-HSCT. EBV was detected in B, T, and NK cells in 20 patients, in B and T cells in 11 patients, and only in B cells in 4 patients. In the 35 patients, the median EBV load in B cells was 2.19×10⁴ copies/ml, significantly higher than that in T cells (4.00×10³ copies/ml, P <0.01) and NK cells (2.85×10² copies/ml, P <0.01). Rituximab (RTX) was administered for 32 patients, resulting in EBV negativity in 32 patients with a median time of 8 days (range: 2-39 days). Post-treatment analysis of 13 patients showed EBV were all negative in B, T, and NK cells. In the four non-transplant patients, the median time to EBV reactivation was 35 days (range: 1-328 days) after diagnosis of the primary disease. EBV was detected in one or two subsets of B, T, or NK cells, but not simultaneously in all three subsets. These patients received a combination chemotherapy targeting at the primary disease, with 3 patients achieving EBV negativity, and the median time to be negative was 40 days (range: 13-75 days). CONCLUSION In hematologic malignancy patients after allo-HSCT, EBV reactivation commonly involves B, T, and NK cells, with a significantly higher viral load in B cells compared to T and NK cells. Rituximab is effective for EBV clearance. In non-transplant patients, EBV reactivation is restricted to one or two lymphocyte subsets, and clearance is slower, highlighting the need for prompt anti-tumor therapy.
Humans ; Hematologic Neoplasms/virology* ; Herpesvirus 4, Human/physiology* ; Epstein-Barr Virus Infections ; Hematopoietic Stem Cell Transplantation ; Virus Activation ; Lymphocyte Subsets/virology* ; Flow Cytometry ; Killer Cells, Natural/virology* ; Male ; Female ; B-Lymphocytes/virology* ; Viral Load ; Adult ; T-Lymphocytes/virology* ; Middle Aged

OBJECTIVE: To assess the safety, efficacy and potential impact of stem cell therapy (SCT) in improving erectile dysfunction (ED). METHODS: A comprehensive search strategy was used to search the literatures on safety and efficacy evaluation of stem cell (SC) in the treatment of ED by human clinical trials from PubMed, Embase and Web of science databases with a search time frame from database creation to July 4, 2024. The exclusion criteria were as follows: reviews, conference abstracts, animal experiments, and duplicate sample literature. RESULTS: The study initially screened 1 773 papers, and 17 were included in the final analysis. These studies involved a total of 269 ED patients, and a variety of sources of stem cells had been used in the treatment of ED, including adipose-derived stem cells, bone marrow-derived stem cells, placental stroma-derived stem cells, umbilical cord-derived stem cells, dental pulp-derived stem cells, and oral mucosa-derived stem cells. All studies were conducted by injecting stem cells into the cavernous body of the penis, but there is no fixed standard for the amount of injection, injection site and number of injections. The optimal treatment mode was still being explored. Patients' International Index of Erectile Function (IIEF) scores and Erection Hardness Score (EHS), peak systolic velocity (PSV), and end diastolic velocity (EDV) improved after treatment. But some studies showed that the efficacy of the treatment diminished with increasing time. No serious adverse effects were reported in any of the studies and none of the adverse effects persisted for a long period of time. The most common adverse effects included injection site reactions, and SCT showed a good safety and tolerability profile. CONCLUSION SCT has the potential to be a promising and innovative regenerative therapy option for ED patients. In the future, with the advancement of stem cell technology, larger randomized controlled studies should continue to be conducted to explore standardized treatments, so as to further evaluate the long-term efficacy and safety of SCT for ED.
Humans ; Erectile Dysfunction/therapy* ; Male ; Stem Cell Transplantation/adverse effects* ; Treatment Outcome ; Stem Cells