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Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload.

Oommen S, Yamada S, Cantero Peral S, Campbell KA, Bruinsma ES, Terzic A, Nelson TJ - Stem Cell Res Ther (2015)

Bottom Line: The RV volume load in PAB-only mice was 24.09±3.9 compared to 11.05±2.09 in the cell group (mm3, P-value<0.005).The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5.Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC's transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.

View Article: PubMed Central - PubMed

Affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. oommen.saji@mayo.edu.

ABSTRACT

Introduction: Stem cell therapy has emerged as potential therapeutic strategy for damaged heart muscles. Umbilical cord blood (UCB) cells are the most prevalent stem cell source available, yet have not been fully tested in cardiac regeneration. Herein, studies were performed to evaluate the cardiovascular safety and beneficial effect of mononuclear cells (MNCs) isolated from human umbilical cord blood upon intramyocardial delivery in a murine model of right ventricle (RV) heart failure due to pressure overload.

Methods: UCB-derived MNCs were delivered into the myocardium of a diseased RV cardiac model. Pulmonary artery banding (PAB) was used to produce pressure overload in athymic nude mice that were then injected intramyocardially with UCB-MNCs (0.4×10^6 cells/heart). Cardiac functions were then monitored by telemetry, echocardiography, magnetic resonance imaging (MRI) and pathologic analysis of heart samples to determine the ability for cell-based repair.

Results: The cardio-toxicity studies provided evidence that UCB cell transplantation has a safe therapeutic window between 0.4 to 0.8 million cells/heart without altering QT or ST-segments or the morphology of electrocardiograph waves. The PAB cohort demonstrated significant changes in RV chamber dilation and functional defects consistent with severe pressure overload. Using cardiac MRI analysis, UCB-MNC transplantation in the setting of PAB demonstrated an improvement in RV structure and function in this surgical mouse model. The RV volume load in PAB-only mice was 24.09±3.9 compared to 11.05±2.09 in the cell group (mm3, P-value<0.005). The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5. Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC's transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.

Conclusions: These findings indicate that human UCB-derived MNCs promote an adaptive regenerative response in the right ventricle upon intramyocardial transplantation in the setting of chronic pressure overload heart failure.

No MeSH data available.


Related in: MedlinePlus

Chronic pressure overload results in morphological and functional changes in the right ventricle. Four weeks after pulmonary artery banding, UCB-MNCs were transplanted into the right ventricle. Body weights and temperatures were recorded at baseline and two, four, six and eight weeks (A, B). There was no significant difference in weight gain between the control, PAB-only and PAB + cells groups. The data depict six animals in each group. (C) Wet weight of whole heart was recorded eight weeks after pulmonary artery banding. A comparison was made between cell transplanted and PAB-only groups. A trend towards increase in heart weight was observed in the cell transplanted group (n = 6; P >0.5). (D) The PAB model was validated prior to cell delivery. After PAB, the right ventricle is exposed to pressure overload by pulmonary outflow tract stenosis resulting in right ventricular dilation (E). PAB, pulmonary artery banding; UCB-MNCs, umbilical cord blood-mononuclear cells.
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Fig4: Chronic pressure overload results in morphological and functional changes in the right ventricle. Four weeks after pulmonary artery banding, UCB-MNCs were transplanted into the right ventricle. Body weights and temperatures were recorded at baseline and two, four, six and eight weeks (A, B). There was no significant difference in weight gain between the control, PAB-only and PAB + cells groups. The data depict six animals in each group. (C) Wet weight of whole heart was recorded eight weeks after pulmonary artery banding. A comparison was made between cell transplanted and PAB-only groups. A trend towards increase in heart weight was observed in the cell transplanted group (n = 6; P >0.5). (D) The PAB model was validated prior to cell delivery. After PAB, the right ventricle is exposed to pressure overload by pulmonary outflow tract stenosis resulting in right ventricular dilation (E). PAB, pulmonary artery banding; UCB-MNCs, umbilical cord blood-mononuclear cells.

Mentions: A surgical PAB model with severe RV pressure and increased volume was created in immunodeficient mice to allow for safety and efficacy studies of h-UCB-derived cells. The average body weight and temperature was marginally decreased between one and two weeks of surgery; however, there was no significant difference in weight gain after four and eight weeks of follow-up (Figure 4A). Significant changes in the body temperature observed between one and four week after surgery (Figure 4B). MNCs administration in the RV showed a marginal increase in heart wet weight; however, the PAB only group did not show any significant increase in heart weight at eight weeks of the study period (Figure 4C). Mice with a pressure overloaded RV demonstrated RV dilation after four weeks as shown by an increased volume in the right ventricular chamber (Figure 4 D, E).Figure 4


Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload.

Oommen S, Yamada S, Cantero Peral S, Campbell KA, Bruinsma ES, Terzic A, Nelson TJ - Stem Cell Res Ther (2015)

Chronic pressure overload results in morphological and functional changes in the right ventricle. Four weeks after pulmonary artery banding, UCB-MNCs were transplanted into the right ventricle. Body weights and temperatures were recorded at baseline and two, four, six and eight weeks (A, B). There was no significant difference in weight gain between the control, PAB-only and PAB + cells groups. The data depict six animals in each group. (C) Wet weight of whole heart was recorded eight weeks after pulmonary artery banding. A comparison was made between cell transplanted and PAB-only groups. A trend towards increase in heart weight was observed in the cell transplanted group (n = 6; P >0.5). (D) The PAB model was validated prior to cell delivery. After PAB, the right ventricle is exposed to pressure overload by pulmonary outflow tract stenosis resulting in right ventricular dilation (E). PAB, pulmonary artery banding; UCB-MNCs, umbilical cord blood-mononuclear cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4416353&req=5

Fig4: Chronic pressure overload results in morphological and functional changes in the right ventricle. Four weeks after pulmonary artery banding, UCB-MNCs were transplanted into the right ventricle. Body weights and temperatures were recorded at baseline and two, four, six and eight weeks (A, B). There was no significant difference in weight gain between the control, PAB-only and PAB + cells groups. The data depict six animals in each group. (C) Wet weight of whole heart was recorded eight weeks after pulmonary artery banding. A comparison was made between cell transplanted and PAB-only groups. A trend towards increase in heart weight was observed in the cell transplanted group (n = 6; P >0.5). (D) The PAB model was validated prior to cell delivery. After PAB, the right ventricle is exposed to pressure overload by pulmonary outflow tract stenosis resulting in right ventricular dilation (E). PAB, pulmonary artery banding; UCB-MNCs, umbilical cord blood-mononuclear cells.
Mentions: A surgical PAB model with severe RV pressure and increased volume was created in immunodeficient mice to allow for safety and efficacy studies of h-UCB-derived cells. The average body weight and temperature was marginally decreased between one and two weeks of surgery; however, there was no significant difference in weight gain after four and eight weeks of follow-up (Figure 4A). Significant changes in the body temperature observed between one and four week after surgery (Figure 4B). MNCs administration in the RV showed a marginal increase in heart wet weight; however, the PAB only group did not show any significant increase in heart weight at eight weeks of the study period (Figure 4C). Mice with a pressure overloaded RV demonstrated RV dilation after four weeks as shown by an increased volume in the right ventricular chamber (Figure 4 D, E).Figure 4

Bottom Line: The RV volume load in PAB-only mice was 24.09±3.9 compared to 11.05±2.09 in the cell group (mm3, P-value<0.005).The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5.Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC's transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.

View Article: PubMed Central - PubMed

Affiliation: General Internal Medicine and Transplant Center, Mayo Clinic, Rochester, MN, USA. oommen.saji@mayo.edu.

ABSTRACT

Introduction: Stem cell therapy has emerged as potential therapeutic strategy for damaged heart muscles. Umbilical cord blood (UCB) cells are the most prevalent stem cell source available, yet have not been fully tested in cardiac regeneration. Herein, studies were performed to evaluate the cardiovascular safety and beneficial effect of mononuclear cells (MNCs) isolated from human umbilical cord blood upon intramyocardial delivery in a murine model of right ventricle (RV) heart failure due to pressure overload.

Methods: UCB-derived MNCs were delivered into the myocardium of a diseased RV cardiac model. Pulmonary artery banding (PAB) was used to produce pressure overload in athymic nude mice that were then injected intramyocardially with UCB-MNCs (0.4×10^6 cells/heart). Cardiac functions were then monitored by telemetry, echocardiography, magnetic resonance imaging (MRI) and pathologic analysis of heart samples to determine the ability for cell-based repair.

Results: The cardio-toxicity studies provided evidence that UCB cell transplantation has a safe therapeutic window between 0.4 to 0.8 million cells/heart without altering QT or ST-segments or the morphology of electrocardiograph waves. The PAB cohort demonstrated significant changes in RV chamber dilation and functional defects consistent with severe pressure overload. Using cardiac MRI analysis, UCB-MNC transplantation in the setting of PAB demonstrated an improvement in RV structure and function in this surgical mouse model. The RV volume load in PAB-only mice was 24.09±3.9 compared to 11.05±2.09 in the cell group (mm3, P-value<0.005). The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5. Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC's transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.

Conclusions: These findings indicate that human UCB-derived MNCs promote an adaptive regenerative response in the right ventricle upon intramyocardial transplantation in the setting of chronic pressure overload heart failure.

No MeSH data available.


Related in: MedlinePlus