Multiple sclerosis iPSC derived-pericytes contract poorly but respond robustly to lesion-relevant environmental stimuli

Multiple sclerosis (MS) is associated with vascular abnormalities including blood-brain-barrier disruption, neurovascular uncoupling and cerebral hypoperfusion. As pericytes regulate vascular integrity and capillary diameter, pericyte dysfunction may contribute to MS pathophysiology. To investigate this, we generated induced pluripotent stem cell-derived pericytes (iPericytes) from individuals with or without relapsing-onset MS (RoMS). RoMS iPericytes exhibited intrinsic, cell-autonomous alterations in gene expression, were larger, and responded poorly to the vasoconstrictor, endothelin-1. Despite intrinsic differences, Control and RoMS iPericytes phagocytosed myelin debris and responded robustly to lesion-relevant stimuli. Hypoxia induced iPericyte proliferation, elongation and angiogenic and immune-related gene expression, while exposure to MS-relevant cytokines (TNFα and IFNγ) exacerbated the endothelin-1-evoked contraction. Both RoMS and cytokine exposure altered the expression of calcium and myosin signalling genes downstream of endothelin-1, including the key contractile regulator MYLK . These data support intrinsic pericyte dysfunction and signalling within MS-lesions as drivers of hypoperfusion and neurodegeneration in MS.