Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes

Abstract

AbstractBrain pericytes maintain blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that human iPSC-derived brain pericytes (iPSC-PC) share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimer’s amyloid-β and tau neurotoxins via lipoprotein receptor. Thus, iPSC-PC may offer a valuable replacement therapy for pericyte-deficient neurological disorders.