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Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury.

Chen LX, Ma SM, Zhang P, Fan ZC, Xiong M, Cheng GQ, Yang Y, Qiu ZL, Zhou WH, Li J - PLoS ONE (2015)

Bottom Line: The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL.Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h.The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China.

ABSTRACT
Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and -bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury.

No MeSH data available.


Related in: MedlinePlus

OPC transplantation inhibits apoptosis in the DG following HI 7 days after transplantation.(A) Apoptotic neurons (white arrows) were visualized by double immunolabeling with antibodies against caspase-3 (red) and NeuN (green). (B) The number of caspase-3+/NeuN+ apoptotic cells increased in HI animals (HI+PBS) compared to sham-operated controls; injection of OPCs (HI+OPC) mitigated this effect. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, HI group vs. sham controls; #P < 0.05, ##P < 0.01 between HI+PBS and HI+OPC groups; n = 6–8 animals per group. Scale bar = 50 μm.
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pone.0115997.g004: OPC transplantation inhibits apoptosis in the DG following HI 7 days after transplantation.(A) Apoptotic neurons (white arrows) were visualized by double immunolabeling with antibodies against caspase-3 (red) and NeuN (green). (B) The number of caspase-3+/NeuN+ apoptotic cells increased in HI animals (HI+PBS) compared to sham-operated controls; injection of OPCs (HI+OPC) mitigated this effect. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, HI group vs. sham controls; #P < 0.05, ##P < 0.01 between HI+PBS and HI+OPC groups; n = 6–8 animals per group. Scale bar = 50 μm.

Mentions: Given the effects on proliferation observed upon OPC transplantation, cell apoptosis was also assessed. To determine whether OPCs could decrease neuronal apoptosis induced by HI, cells were evaluated for caspase-3 and NeuN expression (Fig. 4A). HI injury resulted in a dramatic increase in apoptotic neurons in the DG after 7 days (Fig. 4B) compared to sham control animals. Transplantation of OPCs led to a nearly 50% decrease in the number of caspase-3+/NeuN+ cells (HI+OPC), although the number of apoptotic cells was still higher than in controls (S+OPC). These findings indicate that OPCs inhibit apoptosis of endogenous neurons following HI injury.


Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury.

Chen LX, Ma SM, Zhang P, Fan ZC, Xiong M, Cheng GQ, Yang Y, Qiu ZL, Zhou WH, Li J - PLoS ONE (2015)

OPC transplantation inhibits apoptosis in the DG following HI 7 days after transplantation.(A) Apoptotic neurons (white arrows) were visualized by double immunolabeling with antibodies against caspase-3 (red) and NeuN (green). (B) The number of caspase-3+/NeuN+ apoptotic cells increased in HI animals (HI+PBS) compared to sham-operated controls; injection of OPCs (HI+OPC) mitigated this effect. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, HI group vs. sham controls; #P < 0.05, ##P < 0.01 between HI+PBS and HI+OPC groups; n = 6–8 animals per group. Scale bar = 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4366232&req=5

pone.0115997.g004: OPC transplantation inhibits apoptosis in the DG following HI 7 days after transplantation.(A) Apoptotic neurons (white arrows) were visualized by double immunolabeling with antibodies against caspase-3 (red) and NeuN (green). (B) The number of caspase-3+/NeuN+ apoptotic cells increased in HI animals (HI+PBS) compared to sham-operated controls; injection of OPCs (HI+OPC) mitigated this effect. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, HI group vs. sham controls; #P < 0.05, ##P < 0.01 between HI+PBS and HI+OPC groups; n = 6–8 animals per group. Scale bar = 50 μm.
Mentions: Given the effects on proliferation observed upon OPC transplantation, cell apoptosis was also assessed. To determine whether OPCs could decrease neuronal apoptosis induced by HI, cells were evaluated for caspase-3 and NeuN expression (Fig. 4A). HI injury resulted in a dramatic increase in apoptotic neurons in the DG after 7 days (Fig. 4B) compared to sham control animals. Transplantation of OPCs led to a nearly 50% decrease in the number of caspase-3+/NeuN+ cells (HI+OPC), although the number of apoptotic cells was still higher than in controls (S+OPC). These findings indicate that OPCs inhibit apoptosis of endogenous neurons following HI injury.

Bottom Line: The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL.Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h.The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China.

ABSTRACT
Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and -bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury.

No MeSH data available.


Related in: MedlinePlus