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Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

Wang X, Zhen L, Miao H, Sun Q, Yang Y, Que B, Lopes Lao EP, Wu X, Ren H, Shi S, Lau WB, Ma X, Ma C, Nie S - Theranostics (2015)

Bottom Line: Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype.Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p<0.01 vs pre-infusion), and the treatment effect (delta LVEF) was greater in the bFGF+MSCs group compared to saline (7.43±1.51% versus -10.07±2.94%; p<0.001).Immunofluorescence demonstrated increased cell engraftment and enhanced vascular differentiation in the bFGF+MSCs group compared to MSCs alone (p<0.05).

View Article: PubMed Central - PubMed

Affiliation: 1. Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China;

ABSTRACT

Aim: Basic fibroblast growth factor (bFGF) increases the migration and viability of bone marrow mesenchymal stem cells (MSCs) in vitro. Retrograde coronary venous infusion can provide both increased regional bFGF concentrations and homogeneous cell dissemination. We determined whether retrograde delivery of bFGF enhances the potency of transplanted MSCs for cardiac repair in a canine infarct model.

Methods and results: Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype. A canine infarct model was employed by coronary ligation. One week later, animals were subjected to retrograde infusion of combination bFGF (200ng/mL) and MSCs (1×10(8) cells) (n=5), MSCs (1×10(8) cells, n=5), bFGF (200ng/mL, n=5), or placebo (phosphate-buffered saline, n=3). Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p<0.01 vs pre-infusion), and the treatment effect (delta LVEF) was greater in the bFGF+MSCs group compared to saline (7.43±1.51% versus -10.07±2.94%; p<0.001). Morphologic analysis revealed an increased infarct wall thickness in the bFGF+MSCs group compared to all others (p<0.05), accompanied by increased vascular density and reduced apoptosis. Immunofluorescence demonstrated increased cell engraftment and enhanced vascular differentiation in the bFGF+MSCs group compared to MSCs alone (p<0.05).

Conclusions: Retrograde coronary venous bFGF infusion augments engraftment and differentiation capacity of transplanted MSCs, recovering cardiac function and preventing adverse remodeling. This novel combined treatment and delivery method is a promising strategy for cardiac repair after ischemic injury.

No MeSH data available.


Related in: MedlinePlus

Retrograde infusion of basic fibroblast growth factor (bFGF) enhances mesenchymal stem cells (MSCs) engraftment and differentiation. Representative immunofluorescence images demonstrated coexpression of (A) factor VIII-related antigen (FVIII), (B) α-smooth muscle actin (α-SMA), (C) cardiac troponin I (TnI), and (D) cardiac myosin heavy chain (MHC) in enhanced green fluorescence protein (EGFP) positive cells in the infarct region. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI). (E) The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group than in the MSCs group. (F) The number of labeled cells costained with FVIII and α-SMA was significantly greater in the animals treated with bFGF+MSCs (n=3) compared with MSCs (n=3), indicating enhanced neovascularization by combined therapy. The number of EGFP+ cells coexpressing TnI was not statistically different between the two groups. Scale bars: 100μm (A, C and D); 200μm (B). Histograms represent mean±SEM. *p<0.05 vs MSCs, unpaired Student t test.
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Figure 6: Retrograde infusion of basic fibroblast growth factor (bFGF) enhances mesenchymal stem cells (MSCs) engraftment and differentiation. Representative immunofluorescence images demonstrated coexpression of (A) factor VIII-related antigen (FVIII), (B) α-smooth muscle actin (α-SMA), (C) cardiac troponin I (TnI), and (D) cardiac myosin heavy chain (MHC) in enhanced green fluorescence protein (EGFP) positive cells in the infarct region. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI). (E) The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group than in the MSCs group. (F) The number of labeled cells costained with FVIII and α-SMA was significantly greater in the animals treated with bFGF+MSCs (n=3) compared with MSCs (n=3), indicating enhanced neovascularization by combined therapy. The number of EGFP+ cells coexpressing TnI was not statistically different between the two groups. Scale bars: 100μm (A, C and D); 200μm (B). Histograms represent mean±SEM. *p<0.05 vs MSCs, unpaired Student t test.

Mentions: To address whether bFGF improved MSCs engraftment and survival, the transplanted cells were labeled with EGFP and observed in the myocardium 4 weeks after delivery. The EGFP+ cells localized primarily in the infarct and border zones (Figure 6A-6D). The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group (83.9±9.6/mm2) compared to the MSCs alone group (42.3±7.4/mm2; p<0.05) (Figure 6E).


Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

Wang X, Zhen L, Miao H, Sun Q, Yang Y, Que B, Lopes Lao EP, Wu X, Ren H, Shi S, Lau WB, Ma X, Ma C, Nie S - Theranostics (2015)

Retrograde infusion of basic fibroblast growth factor (bFGF) enhances mesenchymal stem cells (MSCs) engraftment and differentiation. Representative immunofluorescence images demonstrated coexpression of (A) factor VIII-related antigen (FVIII), (B) α-smooth muscle actin (α-SMA), (C) cardiac troponin I (TnI), and (D) cardiac myosin heavy chain (MHC) in enhanced green fluorescence protein (EGFP) positive cells in the infarct region. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI). (E) The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group than in the MSCs group. (F) The number of labeled cells costained with FVIII and α-SMA was significantly greater in the animals treated with bFGF+MSCs (n=3) compared with MSCs (n=3), indicating enhanced neovascularization by combined therapy. The number of EGFP+ cells coexpressing TnI was not statistically different between the two groups. Scale bars: 100μm (A, C and D); 200μm (B). Histograms represent mean±SEM. *p<0.05 vs MSCs, unpaired Student t test.
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Figure 6: Retrograde infusion of basic fibroblast growth factor (bFGF) enhances mesenchymal stem cells (MSCs) engraftment and differentiation. Representative immunofluorescence images demonstrated coexpression of (A) factor VIII-related antigen (FVIII), (B) α-smooth muscle actin (α-SMA), (C) cardiac troponin I (TnI), and (D) cardiac myosin heavy chain (MHC) in enhanced green fluorescence protein (EGFP) positive cells in the infarct region. Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI). (E) The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group than in the MSCs group. (F) The number of labeled cells costained with FVIII and α-SMA was significantly greater in the animals treated with bFGF+MSCs (n=3) compared with MSCs (n=3), indicating enhanced neovascularization by combined therapy. The number of EGFP+ cells coexpressing TnI was not statistically different between the two groups. Scale bars: 100μm (A, C and D); 200μm (B). Histograms represent mean±SEM. *p<0.05 vs MSCs, unpaired Student t test.
Mentions: To address whether bFGF improved MSCs engraftment and survival, the transplanted cells were labeled with EGFP and observed in the myocardium 4 weeks after delivery. The EGFP+ cells localized primarily in the infarct and border zones (Figure 6A-6D). The number of EGFP+ cells was 1-fold higher in the bFGF+MSCs group (83.9±9.6/mm2) compared to the MSCs alone group (42.3±7.4/mm2; p<0.05) (Figure 6E).

Bottom Line: Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype.Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p<0.01 vs pre-infusion), and the treatment effect (delta LVEF) was greater in the bFGF+MSCs group compared to saline (7.43±1.51% versus -10.07±2.94%; p<0.001).Immunofluorescence demonstrated increased cell engraftment and enhanced vascular differentiation in the bFGF+MSCs group compared to MSCs alone (p<0.05).

View Article: PubMed Central - PubMed

Affiliation: 1. Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China;

ABSTRACT

Aim: Basic fibroblast growth factor (bFGF) increases the migration and viability of bone marrow mesenchymal stem cells (MSCs) in vitro. Retrograde coronary venous infusion can provide both increased regional bFGF concentrations and homogeneous cell dissemination. We determined whether retrograde delivery of bFGF enhances the potency of transplanted MSCs for cardiac repair in a canine infarct model.

Methods and results: Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype. A canine infarct model was employed by coronary ligation. One week later, animals were subjected to retrograde infusion of combination bFGF (200ng/mL) and MSCs (1×10(8) cells) (n=5), MSCs (1×10(8) cells, n=5), bFGF (200ng/mL, n=5), or placebo (phosphate-buffered saline, n=3). Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p<0.01 vs pre-infusion), and the treatment effect (delta LVEF) was greater in the bFGF+MSCs group compared to saline (7.43±1.51% versus -10.07±2.94%; p<0.001). Morphologic analysis revealed an increased infarct wall thickness in the bFGF+MSCs group compared to all others (p<0.05), accompanied by increased vascular density and reduced apoptosis. Immunofluorescence demonstrated increased cell engraftment and enhanced vascular differentiation in the bFGF+MSCs group compared to MSCs alone (p<0.05).

Conclusions: Retrograde coronary venous bFGF infusion augments engraftment and differentiation capacity of transplanted MSCs, recovering cardiac function and preventing adverse remodeling. This novel combined treatment and delivery method is a promising strategy for cardiac repair after ischemic injury.

No MeSH data available.


Related in: MedlinePlus