Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Middleton, Ryan; Fournier, Mario; Xu, Xuan; Marbán, Eduardo; Lewis, Michael I.

doi:10.1371/journal.pone.0183557

Cited by 20 publications

(15 citation statements)

References 38 publications

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“…The time course studies revealed that a signi cant increase in RV systolic pressure predated the development of RV hypertrophy in PAH animals, like that described in previous studies [30,34]. This suggests that pressure overload was an important early stimulus to RV hypertrophy in an adaptive fashion.…”

Section: Adaptive Rv Hypertrophysupporting

confidence: 79%

Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Middleton

Fournier²,

Rogers³

et al. 2021

Preprint

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BackgroundPulmonary Arterial Hypertension (PAH) is a progressive cardiopulmonary disease and is characterized by occlusive remodeling of pulmonary arterioles and increased pulmonary vascular resistance. With the onset of PAH, the right ventricle (RV) of the heart adapts to the increased afterload pressure by undergoing adaptive hypertrophic remodeling to maintain adequate blood flow. However, for unknown reasons, maladaptive influences ensue, resulting in impaired RV function with progressive decompensation and right heart failure. Using a rodent model of PAH, we evaluated key signaling pathways mediating cardiac muscle protein synthesis in the RV during the adaptive hypertrophy phase, with preserved right heart function, and the decompensated maladaptive phase, in which right heart failure (RHF) was clinically present.MethodsMale Sprague-Dawley rats were injected subcutaneously with 60mg/kg Monocrotaline (MCT) and RV function was assessed by echocardiography during PAH disease progression. RV tissue was collected during the adaptive and maladaptive phases of PAH and cell signaling pathways involved in survival, hypertrophy, and autophagy, as well as fibrosis and vascularization, were probed using qPCR, Western blotting and histology. Statistical analysis was performed using ANOVA to compare differences between the independent groups and Student-Newman-Keuls test was used to compare differences within independent groups.ResultsAnalysis of protein and gene expression changes in PAH animals identified three key signaling pathways involved in the shift toward maladaptive right heart failure: i) PI3K/Akt/mTOR; ii) GSK-3; iii) MAPK/ERK, as well as IGF-1 regulation. During adaptive hypertrophy, significant increments of phosphorylated proteins in the three signaling pathways were observed with increases in RV fibrosis and decreased capillarity found. In the maladaptive phase, mTORC1 and its downstream effector p-70S6K were significantly activated, contributing to the decreased LC3-I/II ratio, a marker of autophagy inhibition. Additionally, p27, a cyclin-dependent kinase (CDK) inhibitor, which has been recently implicated in regulating mTOR activity to inhibit autophagy and promote heart failure was significantly downregulated. ConclusionWe propose that autophagy inhibition in conjunction with other maladaptive processes reported in the decompensated RV muscle contributes to the genesis of overt RHF in PAH and that a continuum of changes characterizes the adaptive and maladaptive phases in the RV muscle.

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Section: Adaptive Rv Hypertrophysupporting

confidence: 79%

Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Middleton

Fournier²,

Rogers³

et al. 2021

Preprint

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“…CDCs have been shown to promote tissue repair in several preclinical studies, including a DMD mouse model (11,13,(17)(18)(19)(20). Much of the previous work has focused on studying the therapeutic benefits associated with direct myocardial delivery.…”

Section: Discussionmentioning

confidence: 99%

Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice

Rogers¹,

Fournier²,

Sanchez³

et al. 2019

JCI Insight

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“…Due to small sample sizes, statistical tests for comparison were not performed. Categorical data presented as total count and percentage (%), and continuous data are presented as mean ± standard deviation (SD) These anti-inflammatory effects have been demonstrated in animal models of myocardial ischemia, myocarditis, muscular dystrophy, aging, heart failure with preserved ejection fraction, pulmonary arterial hypertension and dilated cardiomyopathy [3,20,21,33,34,42]. Finally, based on preclinical work, a majority of IV CDCs are retained in the lungs [6].…”

Section: Discussionmentioning

confidence: 99%

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series

et al. 2020

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There are no definitive therapies for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, new therapeutic strategies are needed to improve clinical outcomes, particularly in patients with severe disease. This case series explores the safety and effectiveness of intravenous allogeneic cardiosphere-derived cells (CDCs), formulated as CAP-1002, in critically ill patients with confirmed coronavirus disease 2019 . Adverse reactions to CAP-1002, clinical status on the World Health Organization (WHO) ordinal scale, and changes in pro-inflammatory biomarkers and leukocyte counts were analyzed. All patients (n = 6; age range 19-75 years, 1 female) required ventilatory support (invasive mechanical ventilation, n = 5) with PaO 2 /FiO 2 ranging from 69 to 198. No adverse events related to CAP-1002 administration were observed. Four patients (67%) were weaned from respiratory support and discharged from the hospital. One patient remains mechanically ventilated as of April 28th, 2020; all survive. A contemporaneous control group of critically ill COVID-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization. Ferritin was elevated in all patients at baseline (range of all patients 605.43-2991.52 ng/ml) and decreased in 5/6 patients (range of all patients 252.89-1029.90 ng/ml). Absolute lymphocyte counts were low in 5/6 patients at baseline (range 0.26-0.82 × 10 3 / µl) but had increased in three of these five patients at last follow-up (range 0.23-1.02 × 10 3 /µl). In this series of six critically ill COVID-19 patients, intravenous infusion of CAP-1002 was well tolerated and associated with resolution of critical illness in 4 patients. This series demonstrates the apparent safety of CAP-1002 in COVID-19. While this initial experience is promising, efficacy will need to be further assessed in a randomized controlled trial.

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Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Cited by 20 publications

References 38 publications

Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series

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