Dataset Information

Grafted Human iPSC-Derived Neural Progenitor Cells Express Integrins and Extend Long-Distance Axons Within the Developing Corticospinal Tract.

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 ?9?1 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 ?9 integrin subunit is downregulated, adding to the intrinsic inability of axons to regenerate. Our previous work has shown the ?9 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 ?9 integrinwithin the developing rat CST. We demonstrate that human NPCs (hNPCs) express endogenous levels of both ?9 and ?1 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 ?9 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 ?9-expressing hNPCs extend along the endogenous CST and retain expression of ?9 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.

SUBMITTER: Forbes LH

PROVIDER: S-EPMC6380224 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Grafted Human iPSC-Derived Neural Progenitor Cells Express Integrins and Extend Long-Distance Axons Within the Developing Corticospinal Tract.

Forbes Lindsey H LH Andrews Melissa R MR

Frontiers in cellular neuroscience 20190212

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 fa ...[more]

PMID: 30809126

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Project description:The corticospinal tract (CST) plays an important role in controlling voluntary movement. Because the CST has a long trajectory throughout the brain toward the spinal cord, many axon guidance molecules are required to navigate the axons correctly during development. Previously, we found that double-knockout (DKO) mouse embryos lacking the heparan sulfate endosulfatases, Sulf1 and Sulf2, showed axon guidance defects of the CST owing to the abnormal accumulation of Slit2 protein on the brain surface. However, postnatal development of the CST, especially the pyramidal decussation and spinal cord projection, could not be assessed because DKO mice on a C57BL/6 background died soon after birth. We recently found that Sulf1/2 DKO mice on a mixed C57BL/6 and CD-1/ICR background can survive into adulthood and therefore investigated the anatomy and function of the CST in the adult DKO mice. In Sulf1/2 DKO mice, abnormal dorsal deviation of the CST fibers on the midbrain surface persisted after maturation of the CST. At the pyramidal decussation, some CST fibers located near the midline crossed the midline, whereas others located more laterally extended ipsilaterally. In the spinal cord, the crossed CST fibers descended in the dorsal funiculus on the contralateral side and entered the contralateral gray matter normally, whereas the uncrossed fibers descended in the lateral funiculus on the ipsilateral side and entered the ipsilateral gray matter. As a result, the CST fibers that originated from 1 side of the brain projected bilaterally in the DKO spinal cord. Consistently, microstimulation of 1 side of the motor cortex evoked electromyogram responses only in the contralateral forelimb muscles of the wild-type mice, whereas the same stimulation evoked bilateral responses in the DKO mice. The functional consequences of the CST defects in the Sulf1/2 DKO mice were examined using the grid-walking, staircase, and single pellet-reaching tests, which have been used to evaluate motor function in mice. Compared with the wild-type mice, the Sulf1/2 DKO mice showed impaired performance in these tests, indicating deficits in motor function. These findings suggest that disruption of Sulf1/2 genes leads to both anatomical and functional defects of the CST.

Project description:Intracerebral hemorrhage (ICH) prognostication during the acute phase is often subjective among physicians and often affects treatment decisions. The present study explores objective imaging parameters using quantitative corticospinal tract (CST) fiber reconstruction during the acute phase of ICH and correlates these parameters with functional outcome and patient recovery. We prospectively enrolled nonsurgical spontaneous supratentorial ICH patients and obtained an MRI scan on day 5 ± 1. Q-space diffeomorphic reconstruction was performed using DSI Studio, and quantitative anisotropy (QA) was calculated. The CST was reconstructed based on QA. The dichotomized modified Rankin Scale score on day 90 (favorable outcome = 0-2) and Barthel Index (favorable recovery = 100 on day 90 or improvement between discharge and day 90 > 60%) were assessed. Thirty-three patients, median age 72 years (interquartile range (IQR) 64-83), 21 female (64%), 21 (64%) with lobar hemorrhage, median ICH volume on admission 15.0 (IQR 7.0-27.4) mL, were included. Sixteen patients (48%) had a favorable outcome and 24 (73%) had a favorable recovery. The mean number of ipsilesional reconstructed CST fiber pathways was higher in patients with favorable outcomes (153 (standard deviation (SD) 103) vs. 60 (SD 39), p = 0.003) and predicted outcome after adjustment (Exp(B) = 1.016 (95% CI = 1.002-1.030)). QA in the ipsilesional posterior limb of the internal capsule showed a trend towards an association with favorable outcome (Exp(B) = 1.194 (95% CI = 0.991-1.439 (adjusted))). The total (ipsilesional + contralesional) number of reconstructed fiber pathways was associated with favorable recovery (Exp(B) = 1.025 (95% CI = 1.003-1.047 (adjusted))). Quantitative tractography parameters assessed in the acute phase of ICH may represent a promising predictor of long-term outcome and recovery. This might facilitate prognostic evaluation and organization of rehabilitation.

Dataset Information

Grafted Human iPSC-Derived Neural Progenitor Cells Express Integrins and Extend Long-Distance Axons Within the Developing Corticospinal Tract.

Publications

Grafted Human iPSC-Derived Neural Progenitor Cells Express Integrins and Extend Long-Distance Axons Within the Developing Corticospinal Tract.

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