Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Abstract

Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRβ), CD73, CD271, alpha-smooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146⁺ PDGFRβ⁺ Ki67⁺ cells and CD73⁺ CD271⁺ PDGFRβ⁺ Ki67^- cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146⁺ PDGFRβ⁺ Ki67⁺ and CD73⁺ CD271⁺ PDGFRβ⁺ Ki67^- MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146⁺ PDGFRβ⁺ Ki67⁺ MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73⁺ CD271⁺ adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS. Stem Cells Translational Medicine 2017;6:1840-1851.

Keywords: Blood vessels; Central nervous system; Mesenchymal stromal cell; Multiple sclerosis; Neuroinflammation; Pericyte; Perivascular niche.