Grafted human iPSC-derived neural progenitor cells express integrins and extend long-distance axons within the developing corticospinal tract
Grafted human iPSC-derived neural progenitor cells express integrins and extend long-distance axons within the developing corticospinal tract
After spinal cord injury (SCI), regeneration of adult motor axons such as axons
in the corticospinal tract (CST) is severely limited. Alongside the inhibitory lesion
environment, most neuronal subtypes in the mature central nervous system (CNS) are intrinsically unrepairable. With age, expression of growth-promoting proteins in neurons, such as integrins, declines. Integrin receptors allow communication between the extracellular matrix (ECM) and cell cytoskeleton and their expression in axons facilitates growth and guidance throughout the ECM. The a9b1 integrin heterodimer binds to tenascin-C (TN-C), an ECM glycoprotein expressed during development and after injury. In the mature CST however, expression of the a9 integrin subunit is downregulated, adding to the intrinsic inability of axons to regenerate. Our previous work has shown the a9 integrin subunit is not trafficked within axons of mature CST or rubrospinal tracts (RSTs). Thus, here we have utilized human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) to increase expression of a9 integrin within the developing rat CST. We demonstrate that human NPCs (hNPCs) express
endogenous levels of both a9 and b1 integrin subunits as well as cortical neuron
markers such as chicken ovalbumin upstream promoter transcription factor (COUP-TF) interacting protein 2 (Ctip2) and T-box brain 1 (Tbr1). In addition, lentivirus-mediated a9 integrin overexpression in hNPCs resulted in increased neurite outgrowth in the presence of TN-C in vitro. Following transplantation into the sensorimotor cortex of newborn rats, both wild type (WT) and a9-expressing hNPCs extend along the endogenous CST and retain expression of a9 throughout the length of the axonal compartment for up to 8 weeks following transplantation. These data highlight the growth potential of transplanted human iPSCs which may be a future target for regenerative therapies after nervous system injury.
alpha9 integrin, induced pluripotent stem cell, transplantation, neural progenitor cell, sensorimotor cortex
Forbes, Lindsey H.
48ac77a6-3b1e-4be5-ac63-06915b6a8549
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Forbes, Lindsey H.
48ac77a6-3b1e-4be5-ac63-06915b6a8549
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Forbes, Lindsey H. and Andrews, Melissa
(2019)
Grafted human iPSC-derived neural progenitor cells express integrins and extend long-distance axons within the developing corticospinal tract.
Frontiers in Cellular Neuroscience, 13 (26).
(doi:10.3389/fncel.2019.00026).
Abstract
After spinal cord injury (SCI), regeneration of adult motor axons such as axons
in the corticospinal tract (CST) is severely limited. Alongside the inhibitory lesion
environment, most neuronal subtypes in the mature central nervous system (CNS) are intrinsically unrepairable. With age, expression of growth-promoting proteins in neurons, such as integrins, declines. Integrin receptors allow communication between the extracellular matrix (ECM) and cell cytoskeleton and their expression in axons facilitates growth and guidance throughout the ECM. The a9b1 integrin heterodimer binds to tenascin-C (TN-C), an ECM glycoprotein expressed during development and after injury. In the mature CST however, expression of the a9 integrin subunit is downregulated, adding to the intrinsic inability of axons to regenerate. Our previous work has shown the a9 integrin subunit is not trafficked within axons of mature CST or rubrospinal tracts (RSTs). Thus, here we have utilized human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) to increase expression of a9 integrin within the developing rat CST. We demonstrate that human NPCs (hNPCs) express
endogenous levels of both a9 and b1 integrin subunits as well as cortical neuron
markers such as chicken ovalbumin upstream promoter transcription factor (COUP-TF) interacting protein 2 (Ctip2) and T-box brain 1 (Tbr1). In addition, lentivirus-mediated a9 integrin overexpression in hNPCs resulted in increased neurite outgrowth in the presence of TN-C in vitro. Following transplantation into the sensorimotor cortex of newborn rats, both wild type (WT) and a9-expressing hNPCs extend along the endogenous CST and retain expression of a9 throughout the length of the axonal compartment for up to 8 weeks following transplantation. These data highlight the growth potential of transplanted human iPSCs which may be a future target for regenerative therapies after nervous system injury.
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REVISED Manuscript Jan2019 final with figures
- Accepted Manuscript
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fncel-13-00026
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Accepted/In Press date: 22 January 2019
e-pub ahead of print date: 12 February 2019
Keywords:
alpha9 integrin, induced pluripotent stem cell, transplantation, neural progenitor cell, sensorimotor cortex
Identifiers
Local EPrints ID: 428286
URI: http://eprints.soton.ac.uk/id/eprint/428286
ISSN: 1662-5102
PURE UUID: b4954e5d-7217-4eb8-834f-6af14ee548c7
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Date deposited: 20 Feb 2019 17:30
Last modified: 16 Mar 2024 04:28
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Author:
Lindsey H. Forbes
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