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 (PDGFRb), CD73, CD271, alphasmooth 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 1 PDGFRb 1 Ki67 1 cells and CD73 1 CD271 1 PDGFRb 1 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 1 PDGFRb 1 Ki67 1 and CD73 1 CD271 1 PDGFRb 1 Ki67 -MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146 1 PDGFRb 1 Ki67 1 MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73 1 CD271 1 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 SIGNIFICANCE STATEMENTThis immunohistochemical study characterized vascular cells phenotypically similar to pericytes and mesenchymal stromal cells (MSCs) in brain tissue of multiple sclerosis (MS) and healthy persons. We found variations in phenotype, distribution, and proliferation of cells co-expressing markers for MSCs and pericytes that associated with inflammation and MS disease duration. Tissue from long standing MS presented with increased numbers of blood vessels that harbored expanded perivascular areas of cells staining positive for MSCs/pericyte markers. This is the first study to show involvement of MSC/pericyte phenotypic changes in MS pathology and highlights that vessel-targeted treatments may benefit late stage MS.

Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions

“…In spinal cords of individuals with active MS lesions, we found PDGFRβ + stromal cells accumulating outside, but in close proximity to the vascular wall ( Fig. 6c-f), as reported in MS brain lesions 29 .…”

Quantitative chromogenic immunohistochemical image analysis in cellprofiler software

“…Most frequently, this system has been published supporting the quantification of fluorescently stained microscopy specimens. To our knowledge, CellProfiler has only been used for chromogenic quantification in two recent reports . Herein, we demonstrate and validate the value of this system for the identification and quantification of DAB chromogenically stained IHC tissues.…”

“…CellProfiler has been extensively used in the study of fluorescently stained cells and tissues . However, few studies applied the software to the evaluation of chromogenic dye localization . In the current investigation, we primarily developed, validated, and evaluated a CellProfiler pipeline for the detection of CD4 DAB‐IHC staining in oral mucosal biopsies from cGvHD patients and compared against the gold standard manual counting.…”

“…A big advantage to CellProfiler was the ability to devise pipelines for specific antibodies, which once established in a standardized protocol can be repeatedly used, a feature that may be of interest for routine diagnostics . Herein, parameters were optimized to enable not only counting of total number of DAB‐positive cells but also DAB regions and DAB area/area‐masked.…”

Is testosterone perspective available for neurodegenerative diseases?

“…MS is significantly associated with brain atrophy and loss of brain volume [42]. Vascular alterations such as the destabilization of blood brain barrier are the prevalent properties in MS lesions [43]. Gray matter (GM) atrophy has been proposed as a marker for neurodegeneration and disease progression in multiple sclerosis and gray matter lessions in MS are associated with synaptic loss and neuronal cell death [22].…”