Cardiac Progenitor Cells Enhance Neonatal Right Ventricular Function After Pulmonary Artery Banding

Wehman, Brody; Pietris, Nicholas; Bigham, Grace; Siddiqui, Osama; Mishra, Rachana; Li, Tieluo; Aiello, Emily; Jack, Godly; Wang, Ke; Murthi, Sarah B.; Sharma, Sudhish; Kaushal, Sunjay

doi:10.1016/j.athoracsur.2017.04.058

Cited by 20 publications

(25 citation statements)

References 24 publications

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“…The specific pathways involved are an area of active research, but animal models of stem cell therapy have yielded important insights into some of the fundamental tissue-level mechanisms. Pigs treated with CPCs following PA banding showed less fibrosis and increased vascular density in the RV free wall compared to controls (44). A similar increase in vascular density was observed in the previously mentioned ovine models of RV dysfunction.…”

Section: Preclinical Models Of Stem Cell Therapysupporting

confidence: 81%

“…Four weeks following banding and injection, MSC-treated pigs exhibited less RV dilation (as measured by RV enddiastolic area and RV end-systolic area) and improved RV function (as measured by RV fractional area change and RV strain) compared to controls (45). A subsequent experiment evaluating the efficacy of 1 million human CPCs in the same model yielded similar attenuation of RV dilation, as well as improvement in RV function (44).…”

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 86%

“…Stem cell therapies have also been successfully studied in porcine models of pressure overload-induced RV dysfunction secondary to PA banding. In one such model, immunosuppressed juvenile Yorkshire swine underwent PA banding followed immediately by intramyocardial injection of 1 million human MSCs or inert control medium (44,45). Four weeks following banding and injection, MSC-treated pigs exhibited less RV dilation (as measured by RV enddiastolic area and RV end-systolic area) and improved RV function (as measured by RV fractional area change and RV strain) compared to controls (45).…”

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 99%

“…Even in the setting of favorable functional outcomes, preclinical studies are almost universally characterized by minimal retention/differentiation of exogenous stem cells (43,44). These results have driven a shift in paradigm from one based on stem cell engraftment and differentiation to one that focuses on paracrine pathways.…”

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 99%

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Regenerative medicine therapy for single ventricle congenital heart disease

et al. 2018

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One of the most complex forms of congenital heart disease (CHD) involving single ventricle physiology is hypoplastic left heart syndrome (HLHS), characterized by underdevelopment of the left ventricle (LV), mitral and aortic valves, and narrowing of the ascending aorta. The underdeveloped LV is incapable of providing long-term systemic flow, and if left untreated, the condition is fatal. Current treatment for this condition consists of three consecutive staged palliative operations: the first is conducted within the first few weeks of birth, the second between 4 to 6 months, and the third and final surgery within the first 4 years. At the conclusion of the third surgery, systemic perfusion is provided by the right ventricle (RV), and deoxygenated blood flows passively to the pulmonary vasculature. Despite these palliative interventions, the RV, which is ill suited to provide long-term systemic perfusion, is prone to eventual failure. In the absence of satisfying curative treatments, stem cell therapy may represent one innovative approach to the management of RV dysfunction in HLHS patients. Several stem cell populations from different tissues (cardiac and non-cardiac), different age groups (adult- neonate-derived), and different donors (autologous allogeneic), are under active investigation. Preclinical trials in small and large animal models have elucidated several mechanisms by which these stem cells affect the injured myocardium, and are driving the shift from a paradigm based upon cellular engraftment and differentiation to one based primarily on paracrine effects. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of HLHS and other forms of CHD. This article reviews the many stem cell types applied to CHD, their preclinical investigation and the mechanisms by which they might affect RV dysfunction in HLHS patients, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with CHD.

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Section: Preclinical Models Of Stem Cell Therapysupporting

confidence: 81%

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 86%

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 99%

Section: Preclinical Models Of Stem Cell Therapymentioning

confidence: 99%

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Regenerative medicine therapy for single ventricle congenital heart disease

et al. 2018

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“…Human MSCs and c-kit+ CPCs were evaluated in a juvenile porcine model of pressure-induced RV failure achieved by banding the main pulmonary artery. 77 , 78 One million cells were injected intramyocardially into the RV free wall. Both transplanted cell types decreased RV dilation and preserved RV function relative to controls as measured by RV fractional area change and RV strain.…”

Section: Potential Mechanisms Of Rv Dysfunction and Stem Cell Therapymentioning

confidence: 99%

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Bittle

Morales

Deatrick

et al. 2018

Circulation Research

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Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

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Multipotent Human Neonatal Cardiac‐Derived Mesenchymal Stem Cells Modulate Ileitis In Vivo

Gunasekaran

Bury

Sharma

et al. 2023

Advanced Therapeutics

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Transmural skip lesions are pathognomonic for Crohn's disease (CD). Despite advances toward CD treatment, disease recurrence remains a problem. CD requires novel therapies to modulate localized intestinal inflammation and promote intestinal epithelium healing. Human neonatal cardiac‐derived mesenchymal stem cells (nMSCs) demonstrate immune cell modulation accompanied by improved cardiac function recovery in myocardial infarction models. In the established CD‐like ileitis SAMP mouse model, direct skip lesion injection of nMSCs prevents ileal skip lesion growth and significantly down‐regulates the pro‐inflammatory milieu. Significant reduction in the percentage of skip lesion CD68+ macrophages (M1 Mφ, pro‐inflammatory) accompanied by an increase of CD206+ macrophages (M2 Mφ, anti‐inflammatory/pro‐regenerative) is observed in skip lesions following nMSCs injection compared to non‐injected and placebo controls (p < 0.05). Skip lesion size is significantly reduced along with pro‐inflammatory cytokines IFN‐y and TNF‐α, with an increase in intestinal tissue anti‐inflammatory cytokine IL‐10 production. nMSCs are also retained within skip lesions 5 weeks post‐treatment. nMSC administration promotes wound remodeling by modulating inflammatory immune cells and by increasing small bowel gastrointestinal transit with concomitant decreased segment gross pathology score compared to placebo control. Data from this study demonstrate that direct injection of nMSCs into ileal skip lesions attenuates inflammation and improves intestinal physiology.

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Cardiac Progenitor Cells Enhance Neonatal Right Ventricular Function After Pulmonary Artery Banding

Abstract: Intramyocardial injection of c-kit CPCs results in enhanced RV performance relative to control at 30 days postbanding in neonatal pigs. This model is important for further evaluation of c-kit CPCs, including long-term efficacy.

Cited by 20 publications

References 24 publications

Regenerative medicine therapy for single ventricle congenital heart disease

Regenerative medicine therapy for single ventricle congenital heart disease

Stem Cell Therapy for Hypoplastic Left Heart Syndrome

Multipotent Human Neonatal Cardiac‐Derived Mesenchymal Stem Cells Modulate Ileitis In Vivo

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