Interrogating the Potential of Ccn1+ Astrocyte Niches to Drive Angiogenesis after Spinal Cord Injury - ABSTRACT
Spinal Cord Injury (SCI) is a devastating neurological disorder, characterized by disruption to ascending and
descending axonal networks, that can leave people paralyzed for life. After SCI, axons in spared white matter
(WM) regions attempt to undergo short-range sprouting to restore normal neurological function. However,
neuron-extrinsic factors that govern this short-range axon sprouting remain poorly understood. During
development and after injury, new axons spatiotemporally follow new blood vessels, hence intimately linking
axon sprouting to vasculature. Central Nervous System (CNS) vasculature is orchestrated by astrocytes, which
physically interact with endothelia and pericytes to form the gliovascular unit- a tissue niche with indispensable
roles in modulating blood flow and Blood Brain Barrier (BBB) maintenance. Astrocytes are also chief responders
to any CNS insult and undergo highly context dependent changes in morphology, gene expression, and function
in a process collectively referred to as “astrocyte reactivity”. Recent work in stroke and hypoxia have uncovered
necessary roles for reactive astrocytes in restorative angiogenesis, but specific astrocyte-secreted molecules
mediating these effects remain an outstanding question. I have recently identified a novel, spatially restricted
subpopulation of reactive astrocytes defined by persistent upregulation of the powerful pro-angiogenic molecule
CCN Family Member 1(CCN1). In my proposal I will utilize two independent, yet complimentary, aims to test the
hypothesis that Ccn1+ astrocytes demarcate an evolving pro-angiogenic tissue niche, that promotes functional
recovery after SCI by directly governing endothelial cell phenotype including cell proliferation, maturation, or
Notch signaling. In Aim 1 I will analyze a first of its kind longitudinal Spatial Transcriptomics dataset of spared
tissue regions in a mouse hemisection model of SCI (mhSCI) to A) interrogate the molecular evolution of
intraspinal tissue niches harboring Ccn1+ astrocytes, and B) establish a powerful resource for the SCI field. From
this aim I will understand the unique molecular features of Ccn1+ astrocyte niches and computationally infer the
evolution of associated biological processes, signaling cascades, and transcriptional regulators. In Aim 2 I will
complement the computational data from Aim 1 by utilizing a newly generated astrocyte specific CCN1 knockout
mouse for A) behavioral assays of locomotor recovery and B) histological assessment of endothelial cell
phenotype after mhSCI. From this aim I will interrogate the therapeutic potential of CCN1 for SCI and the direct
effect it has on endothelial cell specification. Taken together, this study will uncover the angiogenic potential of
tissue niches harboring Ccn1+ astrocytes and start to provide a glimpse into a potential mechanism of action.
Such findings may have important implications in the development of new therapeutics that are aimed at
providing a more permissive environment for regenerative axon sprouting after SCI.
