Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation

Abstract

Coronary artery disease (CAD) is the single leading cause of death worldwide. Advances in treatment and management have significantly improved patient outcomes. On the other hand, although mortality rates have decreased, more people are left with sequelae that require additional treatment and hospitalization. Moreover, patients with severe nonrevascularizable CAD remain with only the option of heart transplantation, which is limited by the shortage of suitable donors. In recent years, cell-based regenerative therapy has emerged as a possible alternative treatment, with several regenerative medicinal products already in the clinical phase of development and others emerging as competitive preclinical solutions. Recent evidence indicates that pericytes, the mural cells of blood microvessels, represent a promising therapeutic candidate. Pericytes are abundant in the human body, play an active role in angiogenesis, vessel stabilization and blood flow regulation, and possess the capacity to differentiate into multiple cells of the mesenchymal lineage. Moreover, early studies suggest a robustness to hypoxic insult, making them uniquely equipped to withstand the ischemic microenvironment. This review summarizes the rationale behind pericyte-based cell therapy and the progress that has been made toward its clinical application. We present the different sources of pericytes and the case for harvesting them from tissue leftovers of cardiovascular surgery. We also discuss the healing potential of pericytes in preclinical animal models of myocardial ischemia (MI) and current practices to upgrade the production protocol for translation to the clinic. Standardization of these procedures is of utmost importance, as lack of uniformity in cell manufacturing may influence clinical outcome. Stem Cells 2018;36:1295-1310.

Keywords: Cell therapy; Coronary artery disease; Pericytes; Regenerative medicine; Translational medicine.

Figure 1

GMP‐compliant isolation protocol. Finely mince saphenous vein biopsy and digest with Liberase II, at 37°C for up to 2 hours. Filter tissue digest sequentially through a 70 μm, 40 μm, and 30 μm mesh to attain a single cell suspension. Centrifuge cell suspension to separate the cell pellet and then resuspended in column buffer. Incubate suspension with CD31 beads for 30 minutes on ice and filter through magnetic column, keeping the CD31– cell population. Repeat incubation and separation with CD34 beads, retaining the CD31–/CD34+ pericyte population. Culture pericytes in EGM‐2 media on culture plastic coated with gelatin and fibronectin.

Figure 2

Long‐term strategic plan for clinical translation of adventitial pericytes (APCs). 1. SOP for isolation, expansion, and characterization of highly pure human APCs. 2. Mouse LI model. 3. Identification of epigenetic predictors. 4. Immunodeficient and immunocompetent Mice MI model. 5. Mouse MI model using APCs in combination with cardiac stem cells (CSCs). 6. Identification and study of APCs in vivo angiogenic and therapeutic mechanisms. 7. Upgrade of SOP according to acquired data. 8. Swine MI model. Abbreviations: LI, limb ischemia; MI, myocardial Ischemia; SOP, standard operating protocol.