Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure

Agarwal, Udit; Smith, Amanda W.; French, Kristin M.; Boopathy, Archana V.; George, Alex; Trac, David; Brown, Milton E.; Shen, Ming; Jiang, Rong; Fernandez, Janet D.; Kogon, Brian; Kanter, Kirk R.; Alsoufi, Baahaldin; Wagner, Mary B.; Platt, Manu O.; Davis, Michael

doi:10.5966/sctm.2015-0241

Cited by 62 publications

(78 citation statements)

References 28 publications

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“…Our results also demonstrate that hypoxia reverses the phenotype of infant and child CPC-derived exosomes as we observed improved remodeling via increased angiogenesis and decreased fibrosis, suggesting another therapeutic approach in increasing the quality of these exosomes. As our recent study showed donor age-dependent effect of cells in response to right ventricular overload repair 15 , it is possible that hypoxia could alter the reparative phenotype of these cells as well.…”

Section: Discussionmentioning

confidence: 98%

“…Approximately 70–100 mg of right atrial appendage tissue was obtained from children with varied congenital heart diseases, undergoing reconstructive heart surgeries. Human c-kit positive CPCs were isolated and characterized as described previously 15 . In brief, right atrial appendages of the children undergoing cardiac surgeries for various reasons were isolated and transported using Krebs-Ringer solution containing 35 mmol/L NaCl, 4.75 mmol/L KCl, 1.2 mmol/L KH 2 PO 4 , 16 mmol/L Na 2 HPO 4 , 134 mmol/L sucrose, 25 mmol/L NaHCO 3 , 10 mmol/L glucose, 10 mmol/L HEPES, and 30 mmol/L 2,3butanedionemonoxime, pH7.4, with NaOH.…”

Section: Methodsmentioning

confidence: 99%

“…Collagen staining was done as described 15 . In brief, the paraffin embedded sections were dewaxed using histoclear (10 min X 2).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, we have recently shown that younger CPCs have more beneficial effects compared to older CPCs as their efficacy decreases by the time the child reaches 1 year of age 15 . Based upon these observations we hypothesized that exosomes derived from hypoxic and neonatal CPCs can improve ventricular remodeling post-MI.…”

Section: Introductionmentioning

confidence: 99%

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Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

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145

158

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Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. Objective We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Methods and Results Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

“…Collagen staining was done as described 15 . In brief, the paraffin embedded sections were dewaxed using histoclear (10 min X 2).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

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145

158

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“…In summary, we have characterized the electrically induced Ca 2+ signal in CPCs by measuring the amplitude of cytosolic and nuclear Ca 2+ oscillations elicited by electrical stimulation, identified the mechanism by which Ca 2+ oscillations initiate and propagate throughout the cells, and also determined the key proteins involved in this process. Since our experiments were done in human pediatric CPCs, our results may be specific to that population of cells, and further experiments will be necessary to determine whether our results are species- or age-dependent [37]. To our knowledge, this is the first study to have reported the functional effect of acute ex vivo electrical stimulation on human CPCs.…”

Section: Discussionmentioning

confidence: 99%

Electrically Induced Calcium Handling in Cardiac Progenitor Cells

Maxwell

Wagner

Davis

2016

Stem Cells International

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For nearly a century, the heart was viewed as a terminally differentiated organ until the discovery of a resident population of cardiac stem cells known as cardiac progenitor cells (CPCs). It has been shown that the regenerative capacity of CPCs can be enhanced by ex vivo modification. Preconditioning CPCs could provide drastic improvements in cardiac structure and function; however, a systematic approach to determining a mechanistic basis for these modifications founded on the physiology of CPCs is lacking. We have identified a novel property of CPCs to respond to electrical stimulation by initiating intracellular Ca2+ oscillations. We used confocal microscopy and intracellular calcium imaging to determine the spatiotemporal properties of the Ca2+ signal and the key proteins involved in this process using pharmacological inhibition and confocal Ca2+ imaging. Our results provide valuable insights into mechanisms to enhance the therapeutic potential in stem cells and further our understanding of human CPC physiology.

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The Effect of Parent Cell Type on Small Extracellular Vesicle‐Derived Vehicle Functionality

Bheri,

Park,

Hoffman

et al. 2023

Advanced Biology

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Cell therapies involving c‐kit+ progenitor cells (CPCs) and mesenchymal stem cells (MSCs) have been actively studied for cardiac repair. The benefits of such therapies have more recently been attributed to the release of small extracellular vesicles (sEVs) from the parent cells. These sEVs are 30−180 nm vesicles containing protein/nucleic acid cargo encapsulated within an amphiphilic bilayer membrane. Despite their pro‐reparative effects, sEV composition and cargo loading is highly variable, making it challenging to develop robust therapies with sEVs. Synthetic alternatives have been developed to allow cargo modulation, including prior work from the laboratory, to design sEV‐like vehicles (ELVs). ELVs are synthesized from the sEV membrane but allow controlled cargo loading. It is previously shown that loading pro‐angiogenic miR‐126 into CPC‐derived ELVs significantly increases endothelial cell angiogenesis compared to CPC‐sEVs alone. Here, they expand on this work to design MSC‐derived ELVs and study the role of the parent cell type on ELV composition and function. It is found that ELV origin does affect the ELV potency and that ELV membrane composition can affect outcomes. This study showcases the versatility of ELVs to be synthesized from different parent cells and highlights the importance of selecting ELV source cells based on the desired functional outcomes.

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Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure

Cited by 62 publications

References 28 publications

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Electrically Induced Calcium Handling in Cardiac Progenitor Cells

The Effect of Parent Cell Type on Small Extracellular Vesicle‐Derived Vehicle Functionality

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