LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting

Abstract

Injury to the adult mammalian central nervous system induces compensatory plasticity of spared axons—referred to as collateral axon sprouting—that can facilitate neural recovery. The contribution of reactive astrocytes to axon sprouting remains elusive. Here, we sought to investigate the role of axon degeneration-reactive astrocytes in the regulation of collateral axon sprouting that occurs in the mouse spinal cord after unilateral photothrombotic stroke of the primary motor cortex. We identified astrocytic leucine zipper-bearing kinase (LZK) as a positive regulator of astrocyte reactivity to corticospinal axon degeneration. Remarkably, genetic stimulation of astrocyte reactivity, via LZK overexpression in adult astrocytes, enhanced corticospinal axon sprouting. LZK promoted the production of astrocyte-derived ciliary neurotrophic factor (CNTF) that likely enhanced axon growth in mice with astrocytic LZK overexpression after injury. Our finding that LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting highlights the potential of engineering astrocytes to support injury-induced axon plasticity for neural repair.

Capacity of astrocytes to promote axon growth in the injured mammalian central nervous system

“…This is generally true for astrogliosis emanating from acute focal lesion in the gray matter. However, damage to white matter tracts or to neurons from which they originate results in non-scar forming astrogliosis in areas of Wallerian degeneration that can extend over a long distance without tapering off in astrocyte reactivity ( Wang et al, 2009 ; Chen et al, 2022 ).…”

“…These characteristics render them similar to stellate reactive astrocytes, defined as hypertrophic GFAP + reactive astrocytes that can proliferate, but maintain their tiling property and stellate appearance that resembles mature astrocytes in healthy tissue ( Wanner et al, 2013 ; Anderson et al, 2014 ). Genetic stimulation of stellate reactive astrocytes via LZK induction in adult astrocytes enhanced corticospinal axon sprouting in the spinal cord following unilateral photothrombotic stroke of the primary motor cortex ( Chen et al, 2022 ). Furthermore, this phenomenon is injury-dependent ( Chen et al, 2022 ).…”

“…Genetic stimulation of stellate reactive astrocytes via LZK induction in adult astrocytes enhanced corticospinal axon sprouting in the spinal cord following unilateral photothrombotic stroke of the primary motor cortex ( Chen et al, 2022 ). Furthermore, this phenomenon is injury-dependent ( Chen et al, 2022 ). LZK-stimulated stellate reactive astrocytes also produce the cytokine ciliary neurotrophic factor (CNTF) ( Chen et al, 2022 ), which is known to be a sufficient and potent promoter of CNS axon sprouting ( Jin et al, 2015 ).…”

“…Furthermore, this phenomenon is injury-dependent ( Chen et al, 2022 ). LZK-stimulated stellate reactive astrocytes also produce the cytokine ciliary neurotrophic factor (CNTF) ( Chen et al, 2022 ), which is known to be a sufficient and potent promoter of CNS axon sprouting ( Jin et al, 2015 ). While it remains to be determined the extent to which CNTF accounts for the axon sprouting stimulatory effects of LZK and how these stellate reactive astrocytes impact neuronal functions, these findings nevertheless uncovered an exciting positive role of stellate astrogliosis in axon sprouting, with important implications for shaping neural plasticity in an injured CNS.…”

“…Reactive astrocytes produce a number of neurotrophic factors upon spinal cord and brain injuries. These include brain-derived neurotrophic factor (BDNF) known to promote neuronal survival and axon growth ( Dougherty et al, 2000 ; Ikeda et al, 2001 ); ciliary neurotrophic factor (CNTF) ( Lee et al, 1998 ; Tripathi and McTigue, 2008 ; Chen et al, 2022 ) shown to robustly stimulate axon regeneration and sprouting of CNS axons ( Muller et al, 2007 ; Jin et al, 2015 ); nerve growth factor (NGF) ( Goss et al, 1998 ; Krenz and Weaver, 2000 ) that enhances axon regrowth ( Tuszynski et al, 2002 ; Hannila and Kawaja, 2005 ; Mesentier-Louro et al, 2019 ) using reactive astrocytes as a substrate ( Kawaja and Gage, 1991 ); fibroblast growth factor 2 (FGF2) ( do Carmo Cunha et al, 2007 ) shown to promote CNS axon branching ( Szebenyi et al, 2001 ) and sensory axon regeneration ( Lee et al, 2017 ); hepatocyte growth factor (HGF) ( Shimamura et al, 2007 ) capable of increasing CNS axon regrowth ( Kitamura et al, 2007 ; Yamane et al, 2018 ); and insulin-like growth factor 1 (IGF1) ( Yao et al, 1995 ) with potent regeneration-stimulatory activity on corticospinal axons ( Hollis et al, 2009 ; Liu et al, 2017 ). Human spinal cord astrocytes, when stimulated with IL1β to undergo astrogliosis in vitro , also express the growth factors such as FGF2, BDNF, and NGF, adapting an overall axon growth-permissive phenotype ( Teh et al, 2017 ).…”