Faculty Opinions recommendation of Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: functional outcome related to neuroprotection in the striatum.

Abstract Objective: The infusion of bone marrow cells into the damaged brain has been proposed as a new clinical practice for this disorder. Alternatively, hematopoietic growth factors may have a direct role on neural protection or have a mobilizing effect on bone marrow stem/progenitor cells to circulation for brain repair. Based on our previous findings, there are many similarities between megakaryocytes and neurons on functions and antigen expression such as neural marker MAP2, GFAP and Tau, 5-HT2A, 2B and 2C receptors (Stem Cells, 2014). Thrombopoietin (TPO) is a growth factor for megakaryocytic lineage. We postulate that TPO may play a role on neural protection or regeneration. The effect of TPO on nervous system has not been well investigated. Methods: To validate this hypothesis, we investigated the expression and role of TPO/TPO receptors in neural cells and a neonatal rat model of hypoxic-ischemic (HIE) brain damage. Results: To investigate the effect of TPO on in-vivo neural protection, a neonatal rat model of HIE brain damage was established. Brain injury was measured by the percentage weight reduction of the ipsilateral cerebral hemisphere as compared to the contralateral hemisphere. There was significantly less brain atrophy in TPO treated animals (12.0±1.2% and 11.5±1.0%) when compared with the saline control (21.0±1.6% and 24.4±2.2%) at 7 and 28 days post-operation (P<0.05, n=12). The percentage of NSE (Neuron-specific enolase) positive cells in the forelimb area of the cortex in the right hemisphere was significantly higher in the TPO group than that of the saline group (P<0.05, n=12). An improvement in sensory motor functions was also demonstrated after TPO treatment. TPO mRNA was also identified in human cerebral hemispheres, cerebellum, and mouse neural stem cell line C17.2 by RT-PCR methods. TPO protein was detected in human cerebrospinal fluids (n=10) by ELISA. Moreover, TPO receptor (c-mpl) mRNA was identified in human cerebral hemispheres and cerebellum, and C17.2 cells using RT-PCR. The expression of c-mpl protein was also confirmed on neurons in the human cerebral hemispheres, hippocampus, cerebellum, brainstem and spinal cord using immune-cytochemical staining. TPO also showed a stimulating effect on the in-vitro growth of C17.2 cells by the MTT assay. TPO activated the phosphoinositide 3-kinase(PI3K)/Akt signaling pathway which was demonstrated by Western blot. The Akt activation by TPO was inhibited by the PI3-kinase inhibitor LY294002. Conclusions: Our study provided the evidences showing the expression of TPO and TPO receptor (c-mpl) in neural cells and this effect may be mediated by c-mpl and Akt signaling. More importantly, our observation further demonstrated the functional role of TPO on neural protection in a rat model. These findings point to the possibility of a new strategy for treating brain damage by hematopoietic growth factors. Disclosures Yang: National Natural Science Foundation of China: Other: National Natural Science Foundation of China(81270580).

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First Autologous Cell Therapy of Cerebral Palsy Caused by Hypoxic-Ischemic Brain Damage in a Child after Cardiac Arrest—Individual Treatment with Cord Blood

Case Reports in Transplantation ◽

10.1155/2013/951827 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

A. Jensen ◽

E. Hamelmann

Keyword(s):

Cardiac Arrest ◽

Cerebral Palsy ◽

Cord Blood ◽

Brain Damage ◽

Cord Blood Transplantation ◽

Individual Treatment ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Active Rehabilitation

Each year, thousands of children incur brain damage that results in lifelong sequelae. Therefore, based on experimental evidence, we explored the therapeutic potential of human cord blood, known to contain stem cells, to examine the functional neuroregeneration in a child with cerebral palsy after cardiac arrest. The boy, whose cord blood was stored at birth, was 2.5 years old and normally developed when global ischemic brain damage occurred resulting in a persistent vegetative state. Nine weeks later, he received autologous cord blood (91.7 mL, cryopreserved,5.75×10e8mononuclear cells) intravenously. Active rehabilitation (physio- and ergotherapy) was provided daily, follow-up at 2, 5, 12, 24, 30, and 40 months. At 2-months follow-up the boy’s motor control improved, spastic paresis was largely reduced, and eyesight was recovered, as did the electroencephalogram. He smiled when played with, was able to sit and to speak simple words. At 40 months, independent eating, walking in gait trainer, crawling, and moving from prone position to free sitting were possible, and there was significantly improved receptive and expressive speech competence (four-word sentences, 200 words). This remarkable functional neuroregeneration is difficult to explain by intense active rehabilitation alone and suggests that autologous cord blood transplantation may be an additional and causative treatment of pediatric cerebral palsy after brain damage.

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