Targeting pericytes for therapeutic approaches to neurological disorders

Abstract

Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood-brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood-brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the "glial" scar isolating damaged parts of the CNS, and may have stem cell-like properties. Recent studies have suggested that pericytes play a crucial role in neurological diseases, and are thus a therapeutic target in disorders as diverse as stroke, traumatic brain injury, migraine, epilepsy, spinal cord injury, diabetes, Huntington's disease, Alzheimer's disease, diabetes, multiple sclerosis, glioma, radiation necrosis and amyotrophic lateral sclerosis. Here we report recent advances in our understanding of pericyte biology and discuss how pericytes could be targeted to develop novel therapeutic approaches to neurological disorders, by increasing blood flow, preserving blood-brain barrier function, regulating immune cell entry to the CNS, and modulating formation of blood vessels in, and the glial scar around, damaged regions.

Keywords: Alzheimer’s; Blood–brain barrier; Capillary; Diabetes; Ischaemia; Pericyte; Spinal cord injury.

Fig. 1

Functions of CNS pericytes in health. Pericytes form a chain contacting endothelial cells [14], interacting physically with them via a peg and socket structure. Several functions of CNS pericytes are illustrated. (1) BBB formation and maintenance, by regulating tight and adherens junctions, and transcytosis across endothelial cells. (2) Immunoregulation by pericytes regulating the entrance and movement of immune cells such as neutrophils. (3) Capillary diameter (arrows) and hence CBF are regulated by α smooth muscle actin-expressing circumferential processes of pericytes on at least the first four branching order vessels of the capillary bed. (4) Angiogenesis and vessel stabilization are mediated by pericytes during the development and repair of the vasculature. (5) Pericytes can proliferate after conditions like ischaemia, and may also be able to differentiate into other cell types

Fig. 2

Morphology of, and common labelling methods for, pericytes. a Human cortical pericytes, in healthy tissue removed to allow glioma removal. Isolectin B₄ tagged with a green dye is used to label the basement membrane, which extends along capillaries and around pericytes. Pericytes can be seen on straight parts of the capillary and at junctions [white and yellow arrow-heads, respectively, here and in c]. b Human cortical pericyte as in a, labelled for IB₄ (green) and the pericyte marker PDGFRβ. c Cortical capillaries labelled for IB₄ (green) in an NG2-DsRed mouse in which pericytes are red. d Larger views of the top left pericyte show circumferential DsRed-labelled processes (arrows) that will adjust capillary diameter when they contract

Fig. 3

Pericyte responses to brain injury. Injury can: (1) induce pericyte (green) mediated constriction of capillaries; (2) evoke pericyte-mediated regulation of immune function by recruitment of immune cells (leukocytes, blue) to the brain parenchyma, phagocytosis (of green circles) and release of factors (blue open circles) that modulate microglial and macrophage function; and (3) cause loss of BBB function with detachment of pericytes from capillaries and apoptosis, and vessel leakage. Later after injury, pericytes proliferate and migrate to contribute to the scar around the damaged area, and promote blood vessel formation to re-supply the damaged area with nutrients