Empowering human cardiac progenitor cells by P2Y 14 nucleotide receptor overexpression

• Published in: The Journal of physiology 2017-12, Vol.595 (23), p.7135-7148
• Main Authors: Khalafalla, Farid G, Kayani, Waqas, Kassab, Arwa, Ilves, Kelli, Monsanto, Megan M, Alvarez, Jr, Roberto, Chavarria, Monica, Norman, Benjamin, Dembitsky, Walter P, Sussman, Mark A
• Format: Article
• Language: English
• Subjects: Adult; Adult Stem Cells - metabolism; Adult Stem Cells - physiology; Aged; Aged, 80 and over; Cell Proliferation; Cells, Cultured; Cellular Senescence; Female; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - pathology; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP274980

Autologous cardiac progenitor cell (CPC) therapy is a promising approach for treatment of heart failure (HF). There is an unmet need to identify inherent deficits in aged/diseased human CPCs (hCPCs) derived from HF patients in the attempts to augment their regenerative capacity prior to use in the clinical setting. Here we report significant functional correlations between phenotypic properties of hCPCs isolated from cardiac biopsies of HF patients, clinical parameters of patients and expression of the P2Y purinergic receptor (P2Y R), a crucial detector for extracellular UDP-sugars released during injury/stress. P2Y R is downregulated in hCPCs derived from HF patients with lower ejection fraction or diagnosed with diabetes. Augmenting P2Y R expression levels in aged/diseased hCPCs antagonizes senescence and improves functional responses. This study introduces purinergic signalling modulation as a potential strategy to rejuvenate and improve phenotypic characteristics of aged/functionally compromised hCPCs prior to transplantation in HF patients. Autologous cardiac progenitor cell therapy is a promising alternative approach to current inefficient therapies for heart failure (HF). However, ex vivo expansion and pharmacological/genetic modification of human cardiac progenitor cells (hCPCs) are necessary interventions to rejuvenate aged/diseased cells and improve their regenerative capacities. This study was designed to assess the potential of improving hCPC functional capacity by targeting the P2Y purinergic receptor (P2Y R), which has been previously reported to induce regenerative and anti-senescence responses in a variety of experimental models. c-Kit hCPCs were isolated from cardiac biopsies of multiple HF patients undergoing left ventricular assist device implantation surgery. Significant correlations existed between the expression of P2Y R in hCPCs and clinical parameters of HF patients. P2Y R was downregulated in hCPCs derived from patients with a relatively lower ejection fraction and patients diagnosed with diabetes. hCPC lines with lower P2Y R expression did not respond to P2Y R agonist UDP-glucose (UDP-Glu) while hCPCs with higher P2Y R expression showed enhanced proliferation in response to UDP-Glu stimulation. Mechanistically, UDP-Glu stimulation enhanced the activation of canonical growth signalling pathways ERK1/2 and AKT. Restoring P2Y R expression levels in functionally compromised hCPCs via lentiviral-mediated overexpression improved prolife