An Interplay Between Pericytes, Mesenchymal Stem Cells, and Immune Cells in the Process of Tissue Regeneration

Abstract

Immediately after injury, damaged cells elicit tissue regeneration, a healing process that enables optimal renewal and regrowth of injured tissues. Results obtained in a large number of experimental studies suggested that the cross talk between pericytes, mesenchymal stem cells (MSC), tissue-resident stem cells, and immune cells has a crucially important role in the regeneration of injured tissues. Pericytes, MSCs, and immune cells secrete bioactive factors that influence each other's behavior and function. Immune cells produce inflammatory cytokines and chemokines that influence pericytes' migration, proliferation, and transition to MSC. MSC releases immunoregulatory factors that induce the generation of immunosuppressive phenotype in inflammatory immune cells, alleviating detrimental immune responses in injured tissues. MSC also produces various growth factors that influence the differentiation of tissue-resident stem cells into specific cell lineages, enabling the successful regeneration of injured tissues. A better understanding of molecular mechanisms that regulate crosstalk between pericytes, MSC, and immune cells in injured tissues would enable the design of new therapeutic approaches in regenerative medicine. Accordingly, in this review paper, we summarized current knowledge related to the signaling pathways that are involved in the pericytes' activation, pericytes-to-MSC transition, differentiation of tissue-resident stem cells, and MSC-dependent modulation of immune cell-driven inflammation, which are crucially responsible for regeneration of injured tissues.

Keywords: exosomes; immune cells; mesenchymal stem cells; pericytes; tissue regeneration; tissue-resident stem cells.

Figure 1

Therapeutic potential of MSCs. MSCs secrete a range of factors that have immunosuppressive, pro-angiogenic, and trophic effects. These factors work to suppress harmful immune reactions, reduce existing inflammation, promote the formation of new blood vessels, support the growth and differentiation of tissue-specific stem cells, and facilitate improved healing and regeneration of damaged tissues.

Figure 2

Molecular mechanisms responsible for immune cell-dependent detachment of pericytes. Alarmins, released from injured parenchymal cells, directly bind to Toll-like receptors (TLRs) and NOD-like receptors (NLRs) of pericytes and immune cells, initiating phosphorylation and consequent activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). Upon activation, ERK, JNK, and MAPK kinases phosphorylate NF-κB, c-Jun, ATF-2, and CREB transcription factors, which initiate the synthesis of inflammatory cytokines and chemokine. Inflammatory cytokines induce conformational changes in G-protein-coupled receptors (GPCRs) and voltage-gated calcium channels in pericytes, enhancing the synthesis of myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1), which increase actomyosin contractility and pericyte constriction. TGF-β and TNF-α downregulate the expression of integrins on pericytes, promoting their detachment from the blood vessel wall. Chemokines (CXCL12, CXCL8, CCL2, and platelet-derived growth factor (PDGF)) act as chemoattractants that bind to their receptors on pericytes (CXCR4, CCR1, CCR2, and PDGFR-β), activate MAPK and ERK-driven intracellular signaling pathways that promote cytoskeletal rearrangement and cell motility.

Figure 3

Changes in phenotype and function of pericytes during their transition to MSCs. The process of pericyte-to-MSC transition is characterized by increased expression and activity of transcriptional factors which regulate pluripotency and proliferation (Sox9, Oct4, Nanog, and Klf4), immunosuppression and angiomodulation (VEGF, HGF, FGF2, and TGF-β), and by attenuated expression of common pericytes' markers (NG2, platelet- PDGFR-β, and RGS5) and integrins which regulate pericytes' attachment to blood vessel walls.

Figure 4

MSC-dependent modulation of tissue-resident stem cells and immune cells. Upon tissue injury, alarmins, released from injured cells, induce the generation of immunosuppressive phenotype in MSCs. MSC-derived IL-10, TGF-β, and PGE2 suppress the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-12) in macrophages and promote their transition to alternatively activated, anti-inflammatory, and tissue-regenerative phenotype. MSC-primed, alternatively activated (M2) macrophages produce IL-10, TGF-β, IL-4, IL-13, VEGF, FGF-2, FGF-7, and PDGF, which contribute to the resolution of inflammation and the restoration of tissue homeostasis. MSC-sourced IL-10 and TGF-β are mainly responsible for MSC-dependent induction of immunosuppressive, tolerogenic phenotype in DCs in injured tissues. Tolerogenic DCs secrete immunosuppressive cytokines (IL-10, PGE2, TGF-β, IL-4, and IDO), which promote the generation and expansion of immunosuppressive T regulatory cells (Tregs) and alternatively activated macrophages. Also, MSC, in an IDO-dependent manner, induces the generation and expansion of Tregs, importantly contributing to the creation of an immunosuppressive microenvironment. Additionally, MSCs secrete a variety of growth factors (TGF-β, FGF, HGF, PDGF, VEGF, and insulin-like growth factor (IGF)), which synergistically act to promote the proliferation, migration, and differentiation of tissue-resident stem cells, enabling enhanced regeneration of injured tissues.