Highlights•MSCs ameliorate the thymic function of aGVHD patients.•MSCs repaire damaged thymus, thus the incidence of cGVHD decreases.•MSCs have similar efficacy to aGVHD, but our strategy differs with other literature.AbstractRefractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. Forty-seven patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were given at a median dose of 1 × 106 cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD in the MSC group were lower than those in the non-MSC group (P = .045 and P = .005). The ratio of CD3+CD4+/CD3+CD8+ T cells, the frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs), and the levels of signal joint T cell–receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pretreatment. MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse.
Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Patient‐derived organoid (PDO) has great potential in precision oncology, but low success rate, time‐consuming culture, and lack of tumor microenvironment (TME) limit its application. Mesenchymal stromal cells (MSC) accumulate in primary site to support tumor growth and recruit immune cells to form TME. Here, MSC and peripheral blood mononuclear cells (PBMC) coculture is used to construct HCC organoid‐on‐a‐chip mimicking original TME and provide a high‐throughput drug‐screening platform to predict outcomes of anti‐HCC immunotherapies. HCC‐PDOs and PBMC are co‐cultured with MSC and Cancer‐associated fibroblasts (CAF). MSC increases success rate of biopsy‐derived PDO culture, accelerates PDO growth, and promotes monocyte survival and differentiation into tumor‐associated macrophages. A multi‐layer microfluidic chip is designed to achieve high‐throughput co‐culture for drug screening. Compared to conventional PDOs, MSC‐PDO‐PBMC and CAF‐PDO‐PBMC models show comparable responses to chemotherapeutic or targeted anti‐tumor drugs but more precise prediction potential in assessing patients’ responses to anti‐PD‐L1 drugs. Moreover, this microfluidic platform shortens PDO growth time and improves dimensional uniformity of organoids. In conclusion, the study successfully constructs microengineered organoid‐on‐a‐chip to mimic TME for high‐throughput drug screening, providing novel platform to predict immunotherapy response of HCC patients.
Objective
To investigate whether human umbilical cord mesenchymal stem cells-derived exosomes (hucMSC-Ex) could promote liver regeneration after major hepatoectomy in mice and hepatocytes proliferation.
Methods
Using models of 2/3 partial hepatectomy in mice, we evaluated whether hucMSCs-Ex promoted liver regeneration in vivo. Remnant liver to body weight ratio, liver function, hematoxylin and eosin (HE) stain and proliferation cell nuclear antigen (Ki-67) immunohistochemistry of remnant liver tissue were analyzed 24, 48 and 72 h after surgery. Cell counting kit 8 was used to evaluate whether hucMSC-Ex induced hepatocytes proliferation in vitro.
Results
Exosomes ranging from 50-150 nm were isolated frome hucMSCs conditioned medium using differential centrifugation. Western blotting analysis of exosomes showed positive expression of CD63, CD9, and HSP90α. Remnant liver to body weight ratio was significantly increased 48 h and 72 h after hepatectomy in mice injected with hucMSC-Ex as compared with the PBS control group [(3.06±0.44)% vs. (2.67±0.23)%, and (3.18±0.29)% vs. (2.75±0.24)%, P=0.047, 0.013]. Serum alanine aminotransferase (ALT) [(165.0±29.7) vs. (1 596.0±711.9) U/L, and (49.5±18.7) vs. (124.0±39.7) U/L] and aspartate aminotransferase (AST) [(285.0±31.1) vs. (3 030.0±1 249.0) U/L, and (126.3±29.6) vs. (198.3±37.3) U/L] was significantly lower in exosomes group than in control group (P=0.014, 0.014, 0.011, and 0.030 respectively). Besides, less pathological changes were observed after administration of hucMSC-Ex. Increased Ki-67 positive cells 24, 48 and 72 h after hepatectomy were shown in exosomes group compared to PBS control.In vitro study, proliferation of hepatocytes was significantly increased in exosomes (100 μg/ml) group (1.198±0.087 vs. 0.970±0.032, P=0.006).
Conclusion
HucMSC-Ex could promote hepatocyte proliferation and liver regeneration after hepatectomy, but the mechanisms are still neededed to be elucidated.
Key words:
Mesenchymal stem cells; Exosomes; Liver regeneration; Hepatectomy
To evaluate the pollution by polycyclic aromatic hydrocarbons (PAHs) in the surface soil of the core urban area of Lanzhou, 62 topsoil samples were collected from the area. The soil samples were analyzed for the content of 16 priority PAHs, using gas chromatography-mass spectrometry. Descriptive statistical methods were used to characterize contamination by PAHs. An absolute principal component analysis-multiple linear regression (APCS-MLR) model was applied to determine the sources of PAHs in the soil samples, and the accuracy of the model results was verified. Finally, the main influence regions of each source were determined with a geo-statistical method. The results showed that the contents of Σ16 PAHs in the surface soils of Lanzhou ranged from 1069 to 7377 μg ·kg-1, with an average of 2423 μg ·kg-1. High molecular weight PAHs (4-6 rings) were dominant, accounting for 72.81% of the Σ16 PAHs. Verification results of the APCS-MLR model showed that the measured values were in good correspondence with the predicted values, which indicated that the model had good applicability for source apportionment of soil PAHs in the study area. The main sources of PAHs in Lanzhou were traffic emissions (35.42%), petroleum emissions (29.88%), and a mixture of coal and biomass combustion (33.91%). The sources were greatly affected by human activities, and high values were mainly distributed in traffic-intensive and industrial areas. The results indicated that the sources of soil PAHs were complex and influenced by anthropogenic activities in the study area. Stringent control measures should be placed on the sources and areas of influence that contribute to soil PAHs to reduce the emissions and the level of soil pollution resulting from PAHs.
To evaluate the efficacy and safety of bone marrow-derived mesenchymal stem cells (MSC) from a third party donor for secondary poor graft function (PGF) following allogeneic hematopoietic stem cell transplantation(allo-HSCT).Five patients with secondary PGF were treated with MSC at a dose of 1 x 10(6)/kg body weight at a median of 47 days (35 to 61) after secondary PGF. MSC were derived from bone marrow (BM) of HLA-disparate third party donors, cultured in vitro and infused without HSC. If absolute neutrophil cell (ANC) and platelet counts (PLT) did not reach the standardization of > 1.5 x 10(9)/L and > 50.0 x 10(9)/L, respectively, within 28-30 days after the first MSC treatment, a second MSC treatment was required.MSC were infused once in one patient and twice in four patients with an interval of 28 to 30 days. All patients obtained ANC and PLT recovery at a median of 34 (25 to 49) days and 47 (26 to 54) days, respectively, without toxic side effects within follow-up periods of median 761 (204-1491) days. Three patients developed Epstein-Barr virus (EBV) reactivation at 42, 48, 108 days after MSC infusion, respectively and two of the three coverted to posttransplant lymphoproliferative disorders (PTLD).MSC from a third party donor are effective to patients with secondary PGF following allo-HSCT, whether it might increase the risk of EBV reactivation and EBV-associated PTLD need further observation.
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