Molecular mechanisms underlying therapeutic potential of pericytes

Abstract

Background: Pericytes are multipotent cells present in every vascularized tissue in the body. Despite the fact that they are well-known for more than a century, pericytes are still representing cells with intriguing properties. This is mainly because of their heterogeneity in terms of definition, tissue distribution, origin, phenotype and multi-functional properties. The body of knowledge illustrates importance of pericytes in the regulation of homeostatic and healing processes in the body.

Main body: In this review, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in the crosstalk between pericytes and endothelial or immune cells. We highlighted the role of pericytes in the pathogenesis of fibrosis, diabetes-related complications (retinopathy, nephropathy, neuropathy and erectile dysfunction), ischemic organ failure, pulmonary hypertension, Alzheimer disease, tumor growth and metastasis with the focus on their therapeutic potential in the regenerative medicine. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed. Strong evidence for pericytes' participation in physiological, as well as in pathological conditions reveals a broad potential for their therapeutic use. Recently published results obtained in animal studies showed that transplantation of pericytes could positively influence the healing of bone, muscle and skin and could support revascularization. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials.

Conclusion: Critical to further progress in clinical application of pericytes will be identification of tissue specific pericyte phenotype and function, validation and standardization of the procedure for their isolation that will enable establishment of precise clinical settings in which pericyte-based therapy will be efficiently applied.

Keywords: Cell therapy; Pericytes; Vascular disorders.

Fig. 1

Markers of pericytes identification. Due to the heterogeneity of pericytes, several markers were usually used for their identification such as platelet-derived growth factor receptor β (PDGFRβ): receptor with tyrosin kinase activity, involved in pericytes proliferation and recruitment; nerve-glial antigen-2 (NG2): membrane chondroitin sulfate proteoglycan involved in pericyte recruitment to tumor vasculature; CD146: transmembrane glycoprotein that functions as a Ca2 + −independent cell adhesion molecule; the regulator of G-protein signaling-5 (RGS5): a GTPase-activating protein, expressed on activated pericytes during vessel remodeling and tumor development; α-smooth muscle actin (α-SMA) and desmin: structural proteins, important for pericyte contraction and regulation of blood pressure; aminopeptidase N (CD13): membrane zinc-dependent metalloprotease, expressed mainly on brain pericytes; glioma-associated oncogene (Gli1): zinc finger protein, effector of Hedgehog signaling pathway, involved in pericyte-mediated modulation of fibrosis and in the maintenance of peritubular capillary health and T-box transcription factor TBX18 (Tbx18): involved in the development of the heart and coronary vessels

Fig. 2

Signaling pathways between pericytes and ECs. The anatomical relationship and close interactions between pericytes and ECs are important for paracrine or juxtacrine signaling involved in processes of vascular development and stability. Recruitment of pericytes to the endothelium and their crosstalk with ECs is mediated by multiple pathways which are critically involved in embryonic and tumor angiogenesis. Pericyte recruitment to the endothelium is mediated by multiple ligand receptor complexes: PDGF-B/PDGFRb, SDF-1a/CXC4R, HB-EGF/ErbB, and Ang1/Tie-2. The cellular response to TGFb/TGFbR signaling axis is dependent on the composition of the receptor and the relative level of the ligand