Oligodendrocyte Precursor Cells Support Blood-Brain Barrier Integrity via TGF-β Signaling

Abstract

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

“…Similar reports have demonstrated cross‐talk between secreted factors (e.g., apoptosis, inflammation, oxidative stress) (; Brill et al, 2009; Chapman et al, 2015; Lu, Jones, Snyder, & Tuszynski, 2003; Zhang et al, 2015) and neurogenesis following brain insults, including stroke (Kernie and Parent, 2010; Yamashita et al, 2006). We (Hara et al, 2007; Morimoto et al, 2011; Tajiri et al, 2013), and others, have shown the important contribution of neurogenic factors in stroke brain remodeling (Jablonska et al, 2016; Rosell et al, 2013; Seo et al, 2014; Venna, Xu, Doran, Patrizz, & McCullough, 2014). Altogether, these results allude to host neurogenesis and its secreted neurogenic factors as key therapeutic targets of NSI‐189 in affording behavioral and neurostructural benefits in stroke.…”

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…25 It has been increasingly recognized that oligodendrocyte precursor cells themselves also play a pivotal role in promoting BBB integrity by the secretion of transforming growth factor-β1. 93 Moreover, electron microscopy has demonstrated that oligodendrocyte precursor cells and pericytes directly adhere to and communicate with each other via basal lamina to promote their proliferation and differentiation. 94 The above data implicate the impact of disrupted cross talk among BBB cell components in the development of disease pathology.…”

“…Некоторые из этих генов также были идентифицированы при анализе генома людей с ГБВГМ [25]. Было доказано, что клетки-предше-ственники олигодендроцитов сами по себе также играют ключевую роль в обеспечении целостности ГЭБ посред-ством секреции трансформирующего фактора роста-β1 [93]. Кроме того, посредством электронной микроскопии обнаружили, что клетки-предшественники олигодендро-цитов и перициты непосредственно прилегают друг к другу и взаимодействуют через базальную пластинку для обеспечения их пролиферации и дифференцировки [94].…”

Morphogens and blood-brain barrier function in health and disease

“…The authors propose that TGF-b increases BBB integrity through activation of the MAPK/ERK pathway. 69 TGF-b may also be involved in many CNS disorders. AD patients show increased TGF-b levels in the brain, but decreased levels in serum (similar to amyloid b in AD).…”