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Published on: July 10, 2019
Rejuvenation of human cardiac progenitor cells with Pim-1 kinase
Sadia Mohsin1, Mohsin Khan, Jonathan Nguyen
1From the San Diego Heart Research Institute and Biology Department, San Diego State University, CA, and Sharp Memorial Hospital, San Diego, CA.
Insights
Rejuvenating aged human cardiac progenitor cells (hCPCs) with Pim-1 kinase reverses senescence, enhancing their regenerative potential for heart failure therapy. This improves cell proliferation and survival, benefiting older patients with impaired stem cells.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Regenerative Medicine
Background:
- Adoptive transfer of human cardiac progenitor cells (hCPCs) can improve myocardial function in heart failure.
- Cellular senescence, driven by age and comorbidities, impairs hCPC proliferation, survival, and regenerative capacity.
- Rejuvenating senescent hCPCs is crucial for improving regenerative therapy outcomes in a significant patient population.
Purpose of the Study:
- To reverse the phenotypic and functional senescence of hCPCs through ex vivo modification with Pim-1 kinase.
- To investigate the potential of Pim-1 to restore youthful characteristics to aged hCPCs.
Main Methods:
- Isolation of c-kit-positive hCPCs from patient heart biopsy samples.
- Assessment of growth kinetics, telomere lengths, and cell cycle regulator expression.
- Genetic modification of hCPCs using Pim-1 kinase.
Main Results:
- Significant variations in growth kinetics and telomere length were observed among patient-derived hCPCs.
- Slow-growing hCPCs exhibited decreased proliferation, shorter telomeres, and increased senescence markers.
- Pim-1 modification conferred youthful characteristics, including increased proliferation, telomere length, and survival, with reduced senescence markers.
Conclusions:
- Pim-1 kinase effectively ameliorates senescence in hCPCs, rejuvenating their phenotypic and functional properties.
- Pim-1 modification enhances hCPC cellular properties, with greater benefits observed in slow-growing cells.
- Incorporating Pim-1 modification into cell-based therapies can broaden patient inclusion criteria and overcome limitations of aged, senescent hCPCs in heart failure treatment.
Rationale:
Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells.
Objective:
Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1.
Methods And Results:
C-kit-positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers.
Conclusions:
Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC.
