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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 combining basic fibroblast growth factor (bFGF) and mesenchymal stem cells (MSCs) restores cardiac function and prevents left ventricular (LV) remodeling.  Echocardiographic analysis of (A) LV ejection fraction (LVEF), (C) LV end-diastolic volume (LVEDV), and (E) LV end-systolic volume (LVESV) before infusion and 4 weeks after treatment. The treatment effect (final minus pre-infusion parameters) was also evaluated (B, D, and F). (A) LVEF was improved in the bFGF+MSCs group, but remained unchanged in the bFGF group and MSCs group, and decreased in the saline group. The final LVEF and (B) the treatment effect were increased in the MSCs and bFGF+MSCs groups, to greater degree in the latter. (C) All groups exhibited increased LVEDV after infusion, with (D) mild attenuation in the intervention groups (not statistically significant). (E) LVESV remained stable in the intervention groups, but increased in the saline-treated group. At 4 weeks, the combined therapy presented lower LVESV in comparison to saline and bFGF alone groups. (F) The delta changes of LVESV demonstrated significant attenuation in the bFGF alone, MSCs alone, and bFGF+MSCs groups, to greatest degree in the combination group. Histograms (A, C, and E) show pre-infusion vs 4 weeks post-infusion values. Histograms represent mean±SEM. A, C, and E: *p<0.05 vs pre-infusion, paired t test; †p<0.05 vs saline, ‡p<0.05 vs bFGF, between-group repeated measures ANOVA. B, D, and F: *p<0.05 vs saline, 1-way ANOVA with Tukey post hoc test.
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Figure 3: Retrograde infusion of combining basic fibroblast growth factor (bFGF) and mesenchymal stem cells (MSCs) restores cardiac function and prevents left ventricular (LV) remodeling. Echocardiographic analysis of (A) LV ejection fraction (LVEF), (C) LV end-diastolic volume (LVEDV), and (E) LV end-systolic volume (LVESV) before infusion and 4 weeks after treatment. The treatment effect (final minus pre-infusion parameters) was also evaluated (B, D, and F). (A) LVEF was improved in the bFGF+MSCs group, but remained unchanged in the bFGF group and MSCs group, and decreased in the saline group. The final LVEF and (B) the treatment effect were increased in the MSCs and bFGF+MSCs groups, to greater degree in the latter. (C) All groups exhibited increased LVEDV after infusion, with (D) mild attenuation in the intervention groups (not statistically significant). (E) LVESV remained stable in the intervention groups, but increased in the saline-treated group. At 4 weeks, the combined therapy presented lower LVESV in comparison to saline and bFGF alone groups. (F) The delta changes of LVESV demonstrated significant attenuation in the bFGF alone, MSCs alone, and bFGF+MSCs groups, to greatest degree in the combination group. Histograms (A, C, and E) show pre-infusion vs 4 weeks post-infusion values. Histograms represent mean±SEM. A, C, and E: *p<0.05 vs pre-infusion, paired t test; †p<0.05 vs saline, ‡p<0.05 vs bFGF, between-group repeated measures ANOVA. B, D, and F: *p<0.05 vs saline, 1-way ANOVA with Tukey post hoc test.

Mentions: We tested whether bFGF might enhance the potential of transplanted MSCs for cardiac repair by serial echocardiographic analysis at baseline (before MI), 1 week after MI (before infusion), and 4 weeks after infusion (Table 1, Figure 3). The LV structure and function parameters at baseline and before infusion were comparable among the 4 groups (p>0.05) (Table 1, Figure 3A, 3C, and 3E). LV ejection fraction (LVEF) was improved in the bFGF+MSCs group by 11% (p<0.01), but remained unchanged in the bFGF group (p=0.480) and MSCs group (p=0.124), and decreased in the saline group (p<0.01) after 4 weeks (Figure 3A). The treatment effect (delta LVEF) was significantly greater in both the bFGF+MSCs group (7.43±1.51% versus -10.07±2.94%; p<0.001) and MSCs group (4.79±2.47% versus -10.07±2.94%; p<0.01) compared to saline, to greater degree in the combination group (Table 1, Figure 3B).


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 combining basic fibroblast growth factor (bFGF) and mesenchymal stem cells (MSCs) restores cardiac function and prevents left ventricular (LV) remodeling.  Echocardiographic analysis of (A) LV ejection fraction (LVEF), (C) LV end-diastolic volume (LVEDV), and (E) LV end-systolic volume (LVESV) before infusion and 4 weeks after treatment. The treatment effect (final minus pre-infusion parameters) was also evaluated (B, D, and F). (A) LVEF was improved in the bFGF+MSCs group, but remained unchanged in the bFGF group and MSCs group, and decreased in the saline group. The final LVEF and (B) the treatment effect were increased in the MSCs and bFGF+MSCs groups, to greater degree in the latter. (C) All groups exhibited increased LVEDV after infusion, with (D) mild attenuation in the intervention groups (not statistically significant). (E) LVESV remained stable in the intervention groups, but increased in the saline-treated group. At 4 weeks, the combined therapy presented lower LVESV in comparison to saline and bFGF alone groups. (F) The delta changes of LVESV demonstrated significant attenuation in the bFGF alone, MSCs alone, and bFGF+MSCs groups, to greatest degree in the combination group. Histograms (A, C, and E) show pre-infusion vs 4 weeks post-infusion values. Histograms represent mean±SEM. A, C, and E: *p<0.05 vs pre-infusion, paired t test; †p<0.05 vs saline, ‡p<0.05 vs bFGF, between-group repeated measures ANOVA. B, D, and F: *p<0.05 vs saline, 1-way ANOVA with Tukey post hoc test.
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Figure 3: Retrograde infusion of combining basic fibroblast growth factor (bFGF) and mesenchymal stem cells (MSCs) restores cardiac function and prevents left ventricular (LV) remodeling. Echocardiographic analysis of (A) LV ejection fraction (LVEF), (C) LV end-diastolic volume (LVEDV), and (E) LV end-systolic volume (LVESV) before infusion and 4 weeks after treatment. The treatment effect (final minus pre-infusion parameters) was also evaluated (B, D, and F). (A) LVEF was improved in the bFGF+MSCs group, but remained unchanged in the bFGF group and MSCs group, and decreased in the saline group. The final LVEF and (B) the treatment effect were increased in the MSCs and bFGF+MSCs groups, to greater degree in the latter. (C) All groups exhibited increased LVEDV after infusion, with (D) mild attenuation in the intervention groups (not statistically significant). (E) LVESV remained stable in the intervention groups, but increased in the saline-treated group. At 4 weeks, the combined therapy presented lower LVESV in comparison to saline and bFGF alone groups. (F) The delta changes of LVESV demonstrated significant attenuation in the bFGF alone, MSCs alone, and bFGF+MSCs groups, to greatest degree in the combination group. Histograms (A, C, and E) show pre-infusion vs 4 weeks post-infusion values. Histograms represent mean±SEM. A, C, and E: *p<0.05 vs pre-infusion, paired t test; †p<0.05 vs saline, ‡p<0.05 vs bFGF, between-group repeated measures ANOVA. B, D, and F: *p<0.05 vs saline, 1-way ANOVA with Tukey post hoc test.
Mentions: We tested whether bFGF might enhance the potential of transplanted MSCs for cardiac repair by serial echocardiographic analysis at baseline (before MI), 1 week after MI (before infusion), and 4 weeks after infusion (Table 1, Figure 3). The LV structure and function parameters at baseline and before infusion were comparable among the 4 groups (p>0.05) (Table 1, Figure 3A, 3C, and 3E). LV ejection fraction (LVEF) was improved in the bFGF+MSCs group by 11% (p<0.01), but remained unchanged in the bFGF group (p=0.480) and MSCs group (p=0.124), and decreased in the saline group (p<0.01) after 4 weeks (Figure 3A). The treatment effect (delta LVEF) was significantly greater in both the bFGF+MSCs group (7.43±1.51% versus -10.07±2.94%; p<0.001) and MSCs group (4.79±2.47% versus -10.07±2.94%; p<0.01) compared to saline, to greater degree in the combination group (Table 1, Figure 3B).

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