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Reparative effects of neural stem cells in neonatal rats with hypoxic-ischemic injury are not influenced by host sex.

Ashwal S, Ghosh N, Turenius CI, Dulcich M, Denham CM, Tone B, Hartman R, Snyder EY, Obenaus A - Pediatr. Res. (2014)

Bottom Line: We monitored HII evolution (by magnetic resonance imaging, histopathology, behavioral testing) and hNSC fate (migration, replication, viability).Superparamagnetic iron oxide labeling did not influence HII evolution.Our results suggest that hNSC treatment (including using hNSCs that are prelabeled with iron to allow tracking in real time by magnetic resonance imaging) would be equally safe and effective for male and female human newborns with mild-to-moderate HII.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California.

ABSTRACT

Background: Gender is increasingly recognized as an important influence on brain development, disease susceptibility, and response to pharmacologic/rehabilitative treatments. In regenerative medicine, it remains entirely unknown whether there is an interaction between transplanted stem cells and host gender that might bias efficacy and safety in some patients but not others.

Methods: We examined the role of recipient gender in a neonatal rat hypoxic-ischemic injury (HII) model, treated with female human neuronal stem cells (hNSCs), labeled with superparamagnetic iron oxide particles implanted into the contralateral cerebral ventricle. We monitored HII evolution (by magnetic resonance imaging, histopathology, behavioral testing) and hNSC fate (migration, replication, viability).

Results: Recipient gender after implantation did not influence the volume or location of ischemic injury (1, 30, or 90 d) or behavior (90 d). Superparamagnetic iron oxide labeling did not influence HII evolution. Implantation had its greatest benefit on mild/moderate injuries, which remained stable rather than increasing as in severe HII as is the natural history for such lesions.

Conclusion: Our results suggest that hNSC treatment (including using hNSCs that are prelabeled with iron to allow tracking in real time by magnetic resonance imaging) would be equally safe and effective for male and female human newborns with mild-to-moderate HII.

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Immunostaining for hNSC reveals immature and mature cellular phenotypes independent of gender or hNSC labeling statusA1) Immunostaining for human GFAP (hGFAP) identified positive (+) cells in the ipsilateral striatum (Str) adjacent to the lesion that had a mature astrocytic morphology distinct from those seen adjacent to the 3rd ventricle. A2) hGFAP+ cells were also observed within the periventricular region, the median eminence (ME) and the arcuate nucleus (Arc), with fewer hGFAP+ cells were seen in the ventro-medial hypothalamus (VMH). hGFAP+ cells lining the 3rd ventricle had similar morphology to astrocytic radial glia. B1) human-nestin (hNestin) within the contralateral cortex revealed hNSC that exhibited an intermediate filament morphology (arrows). B2) In the ipsilateral hemisphere, hNestin staining was observed adjacent to the ventricle (V), as well as tissues exposed to cerebrospinal fluid, such as cystic regions of the lesion (L), consistent with a more immature cellular phenotype, with only ~50% of these cells nestin+. C1–3) hNestin+ staining (arrows) along the ventricles did not colocalize with hGFAP+ cells (arrows). D1) Abundant endogenous rodent (rGFAP) astrogliosis (X) was observed in the ipsilateral cortex adjacent to the HII lesion. Higher magnification revealed numerous rGFAP+ astrocytes. D2) In contrast, only scattered hGFAP+ cells were observed within the cortical regions adjacent to the HII lesion. High magnification illustrated typical astrocyte morphology in an hGFAP+ cell. D3) No colocalization of human (green) and rat (red) astrocytes was observed. Higher magnification illustrates a single human astrocyte (green) surrounded by rodent astrocytes (red) with no colocalization. (cal bar – 20um)
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Figure 5: Immunostaining for hNSC reveals immature and mature cellular phenotypes independent of gender or hNSC labeling statusA1) Immunostaining for human GFAP (hGFAP) identified positive (+) cells in the ipsilateral striatum (Str) adjacent to the lesion that had a mature astrocytic morphology distinct from those seen adjacent to the 3rd ventricle. A2) hGFAP+ cells were also observed within the periventricular region, the median eminence (ME) and the arcuate nucleus (Arc), with fewer hGFAP+ cells were seen in the ventro-medial hypothalamus (VMH). hGFAP+ cells lining the 3rd ventricle had similar morphology to astrocytic radial glia. B1) human-nestin (hNestin) within the contralateral cortex revealed hNSC that exhibited an intermediate filament morphology (arrows). B2) In the ipsilateral hemisphere, hNestin staining was observed adjacent to the ventricle (V), as well as tissues exposed to cerebrospinal fluid, such as cystic regions of the lesion (L), consistent with a more immature cellular phenotype, with only ~50% of these cells nestin+. C1–3) hNestin+ staining (arrows) along the ventricles did not colocalize with hGFAP+ cells (arrows). D1) Abundant endogenous rodent (rGFAP) astrogliosis (X) was observed in the ipsilateral cortex adjacent to the HII lesion. Higher magnification revealed numerous rGFAP+ astrocytes. D2) In contrast, only scattered hGFAP+ cells were observed within the cortical regions adjacent to the HII lesion. High magnification illustrated typical astrocyte morphology in an hGFAP+ cell. D3) No colocalization of human (green) and rat (red) astrocytes was observed. Higher magnification illustrates a single human astrocyte (green) surrounded by rodent astrocytes (red) with no colocalization. (cal bar – 20um)

Mentions: Our immunohistological data corroborated our MRI findings that neither gender nor hNSC labeling status altered ischemic injury or hNSC volumes. Human GFAP immunoreactive (hGFAP) cells exhibiting classical astrocyte morphology were consistently found in the striatum (Figure 5A1), with the most robust expression observed along the third ventricle adjacent to the ventral hypothalamus (Figure 5A2), exhibiting morphology similar to radial glial cells often proximal to the ventricle (Figure 5A2, expanded).


Reparative effects of neural stem cells in neonatal rats with hypoxic-ischemic injury are not influenced by host sex.

Ashwal S, Ghosh N, Turenius CI, Dulcich M, Denham CM, Tone B, Hartman R, Snyder EY, Obenaus A - Pediatr. Res. (2014)

Immunostaining for hNSC reveals immature and mature cellular phenotypes independent of gender or hNSC labeling statusA1) Immunostaining for human GFAP (hGFAP) identified positive (+) cells in the ipsilateral striatum (Str) adjacent to the lesion that had a mature astrocytic morphology distinct from those seen adjacent to the 3rd ventricle. A2) hGFAP+ cells were also observed within the periventricular region, the median eminence (ME) and the arcuate nucleus (Arc), with fewer hGFAP+ cells were seen in the ventro-medial hypothalamus (VMH). hGFAP+ cells lining the 3rd ventricle had similar morphology to astrocytic radial glia. B1) human-nestin (hNestin) within the contralateral cortex revealed hNSC that exhibited an intermediate filament morphology (arrows). B2) In the ipsilateral hemisphere, hNestin staining was observed adjacent to the ventricle (V), as well as tissues exposed to cerebrospinal fluid, such as cystic regions of the lesion (L), consistent with a more immature cellular phenotype, with only ~50% of these cells nestin+. C1–3) hNestin+ staining (arrows) along the ventricles did not colocalize with hGFAP+ cells (arrows). D1) Abundant endogenous rodent (rGFAP) astrogliosis (X) was observed in the ipsilateral cortex adjacent to the HII lesion. Higher magnification revealed numerous rGFAP+ astrocytes. D2) In contrast, only scattered hGFAP+ cells were observed within the cortical regions adjacent to the HII lesion. High magnification illustrated typical astrocyte morphology in an hGFAP+ cell. D3) No colocalization of human (green) and rat (red) astrocytes was observed. Higher magnification illustrates a single human astrocyte (green) surrounded by rodent astrocytes (red) with no colocalization. (cal bar – 20um)
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Figure 5: Immunostaining for hNSC reveals immature and mature cellular phenotypes independent of gender or hNSC labeling statusA1) Immunostaining for human GFAP (hGFAP) identified positive (+) cells in the ipsilateral striatum (Str) adjacent to the lesion that had a mature astrocytic morphology distinct from those seen adjacent to the 3rd ventricle. A2) hGFAP+ cells were also observed within the periventricular region, the median eminence (ME) and the arcuate nucleus (Arc), with fewer hGFAP+ cells were seen in the ventro-medial hypothalamus (VMH). hGFAP+ cells lining the 3rd ventricle had similar morphology to astrocytic radial glia. B1) human-nestin (hNestin) within the contralateral cortex revealed hNSC that exhibited an intermediate filament morphology (arrows). B2) In the ipsilateral hemisphere, hNestin staining was observed adjacent to the ventricle (V), as well as tissues exposed to cerebrospinal fluid, such as cystic regions of the lesion (L), consistent with a more immature cellular phenotype, with only ~50% of these cells nestin+. C1–3) hNestin+ staining (arrows) along the ventricles did not colocalize with hGFAP+ cells (arrows). D1) Abundant endogenous rodent (rGFAP) astrogliosis (X) was observed in the ipsilateral cortex adjacent to the HII lesion. Higher magnification revealed numerous rGFAP+ astrocytes. D2) In contrast, only scattered hGFAP+ cells were observed within the cortical regions adjacent to the HII lesion. High magnification illustrated typical astrocyte morphology in an hGFAP+ cell. D3) No colocalization of human (green) and rat (red) astrocytes was observed. Higher magnification illustrates a single human astrocyte (green) surrounded by rodent astrocytes (red) with no colocalization. (cal bar – 20um)
Mentions: Our immunohistological data corroborated our MRI findings that neither gender nor hNSC labeling status altered ischemic injury or hNSC volumes. Human GFAP immunoreactive (hGFAP) cells exhibiting classical astrocyte morphology were consistently found in the striatum (Figure 5A1), with the most robust expression observed along the third ventricle adjacent to the ventral hypothalamus (Figure 5A2), exhibiting morphology similar to radial glial cells often proximal to the ventricle (Figure 5A2, expanded).

Bottom Line: We monitored HII evolution (by magnetic resonance imaging, histopathology, behavioral testing) and hNSC fate (migration, replication, viability).Superparamagnetic iron oxide labeling did not influence HII evolution.Our results suggest that hNSC treatment (including using hNSCs that are prelabeled with iron to allow tracking in real time by magnetic resonance imaging) would be equally safe and effective for male and female human newborns with mild-to-moderate HII.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California.

ABSTRACT

Background: Gender is increasingly recognized as an important influence on brain development, disease susceptibility, and response to pharmacologic/rehabilitative treatments. In regenerative medicine, it remains entirely unknown whether there is an interaction between transplanted stem cells and host gender that might bias efficacy and safety in some patients but not others.

Methods: We examined the role of recipient gender in a neonatal rat hypoxic-ischemic injury (HII) model, treated with female human neuronal stem cells (hNSCs), labeled with superparamagnetic iron oxide particles implanted into the contralateral cerebral ventricle. We monitored HII evolution (by magnetic resonance imaging, histopathology, behavioral testing) and hNSC fate (migration, replication, viability).

Results: Recipient gender after implantation did not influence the volume or location of ischemic injury (1, 30, or 90 d) or behavior (90 d). Superparamagnetic iron oxide labeling did not influence HII evolution. Implantation had its greatest benefit on mild/moderate injuries, which remained stable rather than increasing as in severe HII as is the natural history for such lesions.

Conclusion: Our results suggest that hNSC treatment (including using hNSCs that are prelabeled with iron to allow tracking in real time by magnetic resonance imaging) would be equally safe and effective for male and female human newborns with mild-to-moderate HII.

Show MeSH
Related in: MedlinePlus