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Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1^G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.

SUBMITTER: Ambrozkiewicz KA

PROVIDER: S-EPMC8901633 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

Ambrożkiewicz Karolina A KA Kozłowska Urszula U Haesler Valerie V Barnea Eytan R ER Mueller Martin M Kurpisz Maciej M

Scientific reports 20220307 1

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1<sup>G93A</ ...[more]

PMID: 35256767

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Project description:IntroductionCortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.MethodsTo evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.ResultsBased on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.DiscussionIndividuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.

Project description:BackgroundPreterm white matter injury (PWMI) is the most common type of brain injury in preterm infants, in which, oligodendrocyte progenitor cells (OPCs) are predominantly damaged. In this study, human OPCs (hOPCs) were administered to a fetal goat model of PWMI to examine the differentiation potential and therapeutic effects of the cells on PWMI.MethodsPreterm goat fetuses were subjected to hypoxic-ischemia (HI) via intermittent umbilical cord occlusion (5 min × 5). Twenty million hOPCs were administered via a nasal catheter 12 h after an HI insult, and brain tissues were collected 14 or 21 days after the HI insult. Myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) were detected by immunofluorescence and western blotting techniques. The percentage of myelinated nerve fibers and g-ratio were examined using transmission electron microscopy. Inflammatory cells were detected by immunohistochemistry. Inflammatory and neurotrophic factors were measured using enzyme-linked immunosorbent assay.ResultsOur results showed that intermittent umbilical cord occlusion induced PWMI in fetal goats. Transplanted hOPCs can survive in periventricular and subcortical white matter. Further, transplanted hOPCs expressed markers of mature oligodendrocytes (MBP and MAG) and few cells expressed markers of preoligodendrocytes (NG2 and A2B5), suggesting that these cells can differentiate into mature oligodendrocytes in the brain. In addition, hOPCs administration increased MBP and MAG levels, percentage of myelinated nerve fibers, and thickness of the myelin sheath, indicating a reduction in PWMI. Furthermore, hOPCs did not increase the inflammatory response after HI. Interestingly, hOPC administration decreased tumor necrosis factor-alpha and increased glial-derived neurotrophic factor and brain-derived neurotrophic factor levels after HI, suggesting that additional mechanisms mediate the inflammatory microenvironment and neuroprotective effects.ConclusionsExogenous hOPCs can differentiate into mature oligodendrocytes in fetal goats and alleviate HI-induced PWMI. Transplantation of hOPCs is a promising strategy for treating PWMI.

Dataset Information

Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

Publications

Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

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