Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-ß1 signaling in coxsackievirus B3-induced cardiomyopathy.

Myocardial fibrosis plays an important role in coxsackievirus B3 (CVB3) induced dilated cardiomyopathy. Excessive transforming growth factor (TGF)-ß1 contributes to a pathologic excess of tissue fibrosis. We investigated the effect of astragaloside IV on myocardial fibrosis in CVB3-induced dilated cardiomyopathy. BALB/c mice were inoculated with CVB3 to induce acute viral myocarditis on day 7 (acute VMC group), monthly for 3 months to induce chronic myocarditis (chronic VMC group), and monthly for 9 months to induce dilated cardiomyopathy (DCM group). The same method was used for the DCM+Astra group as that of the DCM group, but former group was given with astragaloside IV-containing drinking water. Compared to DCM group, astragaloside IV treatment significantly increased the survival rate. Histological findings and the collagen volume fraction showed that astragaloside IV decreased fibrosis in heart tissues. Astragaloside IV decreased the level of the serum carboxy-terminal propeptide of procollagen type I (PICP) and the ratio of PICP/ N-terminal type I procollagen propeptide (PINP). Ameliorated myocardial fibrosis was consistent with the downregulated expression of TGF-ß1 and its downstream pSmad2/3 and Smad4 in the myocardium of the DCM+Astra group compared to the DCM group. The level of type I collagen was lower in the DCM+Astra group than the DCM group. The same effect was found in the in vitro study. These findings showed that astragaloside IV had a potent preventive effect on myocardial fibrosis in CVB3-induced dilated cardiomyopathy that might be due to downregulation of TGF-ß1-Smad signaling.

Kidney-derived mesenchymal stromal cells modulate dendritic cell function to suppress alloimmune responses and delay allograft rejection.

BACKGROUND: Mesenchymal stromal cells (MSCs) are multipotent cells with immunoregulatory capacity that are present in most adult organs. We previously demonstrated that co-culture of C57BL/6 kidney-derived MSCs (KSCs) in syngeneic bone marrow-derived dendritic cell (DC) culture induced a DC phenotype (KSC-DC) with reduced major histocompatibility complex (MHC) class II/increased CD80 expression and ability to suppress T-cell responses. METHODS: To study their effects on allogeneic DCs, C57BL/6 KSCs were added to incipient BALB/c DC culture, with surface expression of MHC class II/CD80 measured by fluorescence-activated cell sorting. The ability to stimulate T-cell responses was then assessed in an allogeneic mixed leukocyte response. Next, we isolated either BALB/c (donor) or C57BL/6 (recipient) KSC-DCs from co-culture and measured the tempo of rejection after cotransplantation with islet grafts in a mouse model of islet transplantation. Finally, we measured the effects of KSC-DC stimulation on B-cell proliferation and IgM/IgG production in allogeneic cultures. RESULTS: C57BL/6 KSCs induced a BALB/c DC phenotype with significantly decreased MHC class II, increased CD80 expression, and decreased T-cell stimulatory capacity in the mixed leukocyte response (P<0.01 vs. control). Cotransplantation of donor (BALB/c) but not recipient (C57BL/6) KSC-DCs resulted in significant delay of rejection after islet transplantation (P<0.01 vs. control). Finally, stimulation by KSC-DCs resulted in significantly reduced B-cell proliferation and antibody production in allogeneic culture (P<0.01 vs. control). CONCLUSIONS: Our results highlight an important mechanism of MSC-based immunotherapy and its potential for use in clinical transplantation as prevention of rejection and possibly sensitization.