Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications

Abstract

Pericytes are mural vascular cells found predominantly on the abluminal wall of capillaries, where they contribute to the maintenance of capillary structural integrity and vascular permeability. Generally quiescent cells in the adult, pericyte activation and proliferation occur during both physiological and pathological vascular and tissue remodeling. A considerable body of research indicates that pericytes possess attributes of a multipotent adult stem cell, as they are capable of self-renewal as well as commitment and differentiation into multiple lineages. However, pericytes also display phenotypic heterogeneity and recent studies indicate that lineage potential differs between pericyte subpopulations. While numerous microenvironmental cues and cell signaling pathways are known to regulate pericyte functions, the roles that metabolic pathways play in pericyte quiescence, self-renewal or differentiation have been given limited consideration to date. This review will summarize existing data regarding pericyte metabolism and will discuss the coupling of signal pathways to shifts in metabolic pathway preferences that ultimately regulate pericyte quiescence, self-renewal and trans-differentiation. The association between dysregulated metabolic processes and development of pericyte pathologies will be highlighted. Despite ongoing debate regarding pericyte classification and their functional capacity for trans-differentiation in vivo, pericytes are increasingly exploited as a cell therapy tool to promote tissue healing and regeneration. Ultimately, the efficacy of therapeutic approaches hinges on the capacity to effectively control/optimize the fate of the implanted pericytes. Thus, we will identify knowledge gaps that need to be addressed to more effectively harness the opportunity for therapeutic manipulation of pericytes to control pathological outcomes in tissue remodeling.

Mapping the transcriptomic changes of endothelial compartment in human hippocampus across aging and mild cognitive impairment

“…The involvement of EPCs could be possible given their ability for homing and further differentiation ( Kioi et al, 2010 ; Wei et al, 2019 ). Moreover, endothelial cells could be also generated during neovascularization by trans-differentiation from mesenchymal cells ( Balaji et al, 2013 ) and/or from pericytes ( Nwadozi et al, 2020 ).…”

Parallels between the Developing Vascular and Neural Systems: Signaling Pathways and Future Perspectives for Regenerative Medicine

“…The ligand, released from angiogenic endothelial cells, binds to its receptor PDGFRB expressed by developing pericytes. [ 1 , 36 , 37 ]…”

“…[ 27 ] Studies have shown that pericytes are dominantly quiescent in established blood vessel networks, but can proliferate and differentiate into progenitor cells, when said network is being remodeled. [ 37 ] They have been shown to differentiate into a vast array of lineages, including those of mesenchymal and neural stem cells. [ 36 , 37 ] Interestingly, in the adult brain, pericytes have been found directly adjacent to the tip cells of elongating blood vessels, suggesting a crosstalk between the two cell types in the CNS.…”

Engineering Brain-Specific Pericytes from Human Pluripotent Stem Cells

“…There are many similarities in metabolism shifts with PC phenotype compared to MSCs and microglia. 71,72 For these cells, glycolysis is associated with more primitive phenotype, while the lineage-committed differentiation uses more oxidative phosphorylation, showing the upregulation of mitochondrial capacity. [73][74][75][76][77] In particular, Notch signaling is involved in the regulation of PC metabolism and quiescence, for example, through the downregulation of glycolytic enzymes (e.g., PFKFB3).…”

“…Hyperglycemia elevates flux through the hexosamine pathway, and increased levels of fatty acids result in insulin resistance and lipid toxicity. 71…”