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White matter injury restoration after stem cell administration in subcortical ischemic stroke.

Otero-Ortega L, Gutiérrez-Fernández M, Ramos-Cejudo J, Rodríguez-Frutos B, Fuentes B, Sobrino T, Hernanz TN, Campos F, López JA, Cerdán S, Vázquez J, Díez-Tejedor E - Stem Cell Res Ther (2015)

Bottom Line: The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group.Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.These findings are associated with improved functional recovery after stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. laura.otero@salud.madrid.org.

ABSTRACT

Introduction: Despite its high incidence, nerve fiber (axon and myelin) damage after cerebral infarct has not yet been extensively investigated. The aim of this study was to investigate white matter repair after adipose-derived mesenchymal stem cell (ADMSC) administration in an experimental model of subcortical stroke. Furthermore, we aimed to analyze the ADMSC secretome and whether this could be implicated in this repair function.

Methods: An animal model of subcortical ischemic stroke with white matter affectation was induced in rats by injection of endothelin-1. At 24 hours, 2 × 10(6) ADMSC were administered intravenously to the treatment group. Functional evaluation, lesion size, fiber tract integrity, cell death, proliferation, white matter repair markers (Olig-2, NF, and MBP) and NogoA were all studied after sacrifice (7 days and 28 days). ADMSC migration and implantation in the brain as well as proteomics analysis and functions of the secretome were also analyzed.

Results: Neither ADMSC migration nor implantation to the brain was observed after ADMSC administration. In contrast, ADMSC implantation was detected in peripheral organs. The treatment group showed a smaller functional deficit, smaller lesion area, less cell death, more oligodendrocyte proliferation, more white matter connectivity and higher amounts of myelin formation. The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group. Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.

Conclusions: White matter integrity in subcortical stroke is in part restored by ADMSC treatment; this is mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery after stroke.

No MeSH data available.


Related in: MedlinePlus

ADMSC treatment reduced infarct size and increased fiber tract and myelin integrity after subcortical white matter damage. a Morphological study by CryoMyelin staining identified the zone of the lesion as an area of white matter injury located in the subcortical zone, showing restored myelinated axons in the ADMSC-treated animals. b Quantification of mean ROI intensity of the CryoMyelin staining. Stroked line indicates ROI; yellow line indicates a representative longitudinal profile of pixel intensity. c Comparative image analysis T2-weighted MRI and tractography at 1, 7 and 28 days showed a progressive reduction in white matter infarct size in controls and treated animals. Detail of tractography image in the lesion is given below showing augmented connectivity of fiber tracts in ADMSC-treated animals at 28 days. d Quantitative analysis of MRI images showed that ADMSC therapy reduced lesion size at 28 days compared to the controls (p < 0.05). Data are shown as mean ± SEM; *p < 0.05; n = 6 animals, 10 sections each per group. ADMSC adipose-derived mesenchymal stem cells, d days, MRI magnetic resonance image, ROI region of interest
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Fig3: ADMSC treatment reduced infarct size and increased fiber tract and myelin integrity after subcortical white matter damage. a Morphological study by CryoMyelin staining identified the zone of the lesion as an area of white matter injury located in the subcortical zone, showing restored myelinated axons in the ADMSC-treated animals. b Quantification of mean ROI intensity of the CryoMyelin staining. Stroked line indicates ROI; yellow line indicates a representative longitudinal profile of pixel intensity. c Comparative image analysis T2-weighted MRI and tractography at 1, 7 and 28 days showed a progressive reduction in white matter infarct size in controls and treated animals. Detail of tractography image in the lesion is given below showing augmented connectivity of fiber tracts in ADMSC-treated animals at 28 days. d Quantitative analysis of MRI images showed that ADMSC therapy reduced lesion size at 28 days compared to the controls (p < 0.05). Data are shown as mean ± SEM; *p < 0.05; n = 6 animals, 10 sections each per group. ADMSC adipose-derived mesenchymal stem cells, d days, MRI magnetic resonance image, ROI region of interest

Mentions: MRI analysis showed no significant difference in infarct size between the treatment and control groups after 1 and 7 days. However, the infarct size was significantly smaller in the treatment group than in the control group after 28 days (0.12 ± 0.01 vs. 0.6 ± 0.26, p < 0.05) (Fig. 3).Fig. 3


White matter injury restoration after stem cell administration in subcortical ischemic stroke.

Otero-Ortega L, Gutiérrez-Fernández M, Ramos-Cejudo J, Rodríguez-Frutos B, Fuentes B, Sobrino T, Hernanz TN, Campos F, López JA, Cerdán S, Vázquez J, Díez-Tejedor E - Stem Cell Res Ther (2015)

ADMSC treatment reduced infarct size and increased fiber tract and myelin integrity after subcortical white matter damage. a Morphological study by CryoMyelin staining identified the zone of the lesion as an area of white matter injury located in the subcortical zone, showing restored myelinated axons in the ADMSC-treated animals. b Quantification of mean ROI intensity of the CryoMyelin staining. Stroked line indicates ROI; yellow line indicates a representative longitudinal profile of pixel intensity. c Comparative image analysis T2-weighted MRI and tractography at 1, 7 and 28 days showed a progressive reduction in white matter infarct size in controls and treated animals. Detail of tractography image in the lesion is given below showing augmented connectivity of fiber tracts in ADMSC-treated animals at 28 days. d Quantitative analysis of MRI images showed that ADMSC therapy reduced lesion size at 28 days compared to the controls (p < 0.05). Data are shown as mean ± SEM; *p < 0.05; n = 6 animals, 10 sections each per group. ADMSC adipose-derived mesenchymal stem cells, d days, MRI magnetic resonance image, ROI region of interest
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4513704&req=5

Fig3: ADMSC treatment reduced infarct size and increased fiber tract and myelin integrity after subcortical white matter damage. a Morphological study by CryoMyelin staining identified the zone of the lesion as an area of white matter injury located in the subcortical zone, showing restored myelinated axons in the ADMSC-treated animals. b Quantification of mean ROI intensity of the CryoMyelin staining. Stroked line indicates ROI; yellow line indicates a representative longitudinal profile of pixel intensity. c Comparative image analysis T2-weighted MRI and tractography at 1, 7 and 28 days showed a progressive reduction in white matter infarct size in controls and treated animals. Detail of tractography image in the lesion is given below showing augmented connectivity of fiber tracts in ADMSC-treated animals at 28 days. d Quantitative analysis of MRI images showed that ADMSC therapy reduced lesion size at 28 days compared to the controls (p < 0.05). Data are shown as mean ± SEM; *p < 0.05; n = 6 animals, 10 sections each per group. ADMSC adipose-derived mesenchymal stem cells, d days, MRI magnetic resonance image, ROI region of interest
Mentions: MRI analysis showed no significant difference in infarct size between the treatment and control groups after 1 and 7 days. However, the infarct size was significantly smaller in the treatment group than in the control group after 28 days (0.12 ± 0.01 vs. 0.6 ± 0.26, p < 0.05) (Fig. 3).Fig. 3

Bottom Line: The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group.Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.These findings are associated with improved functional recovery after stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. laura.otero@salud.madrid.org.

ABSTRACT

Introduction: Despite its high incidence, nerve fiber (axon and myelin) damage after cerebral infarct has not yet been extensively investigated. The aim of this study was to investigate white matter repair after adipose-derived mesenchymal stem cell (ADMSC) administration in an experimental model of subcortical stroke. Furthermore, we aimed to analyze the ADMSC secretome and whether this could be implicated in this repair function.

Methods: An animal model of subcortical ischemic stroke with white matter affectation was induced in rats by injection of endothelin-1. At 24 hours, 2 × 10(6) ADMSC were administered intravenously to the treatment group. Functional evaluation, lesion size, fiber tract integrity, cell death, proliferation, white matter repair markers (Olig-2, NF, and MBP) and NogoA were all studied after sacrifice (7 days and 28 days). ADMSC migration and implantation in the brain as well as proteomics analysis and functions of the secretome were also analyzed.

Results: Neither ADMSC migration nor implantation to the brain was observed after ADMSC administration. In contrast, ADMSC implantation was detected in peripheral organs. The treatment group showed a smaller functional deficit, smaller lesion area, less cell death, more oligodendrocyte proliferation, more white matter connectivity and higher amounts of myelin formation. The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group. Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.

Conclusions: White matter integrity in subcortical stroke is in part restored by ADMSC treatment; this is mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery after stroke.

No MeSH data available.


Related in: MedlinePlus