Cord Blood for Neonatal Hypoxic-ischemic Encephalopathy

January 12th, 2011 | Posted by admin in Research

The purpose of this pilot study is to evaluate the safety and feasibility of infusions of autologous (the patient’s own)umbilical cord blood cells in term gestation newborn infants with hypoxic-ischemic encephalopathy. For this study, infants who have signs of moderate to severe encephalopathy at birth whose mothers have previously consented to providing cord blood cells for the Carolinas Cord Blood Bank or other public or private bank that uses accepted standards for collection and handling of cells, or provided verbal consent for cord blood collection for the possibility of their baby’s participation in this trial, can receive their own cord blood cells if an adequate number of cells that meet Carolinas Cord Blood Bank Quality standards are available in the first 14 postnatal days. Study activities also include serial blood draws concurrent with clinically indicated blood draws with a total volume of no more than 5 milliliters (1 teaspoon) from all study related tests. Babies will be followed for neurodevelopmental outcome at 4 – 6 and 9 – 12 months at Duke’s Special Infant Care Clinic. MRI’s will be obtained between postnatal weeks 1 and 4, and, for study purposes at 4 – 6 postnatal months.

Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function.

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

Birth asphyxia is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. We show that a single mesenchymal stem cell treatment at 3 d (MSC-3) after neonatal hypoxia-ischemia (HI) in postnatal day 9 mice improved sensorimotor function and reduced lesion size. A second MSC treatment at 10 d after HI (MSC-3+10) further enhanced sensorimotor improvement and recovery of MAP2 and MBP (myelin basic protein) staining. Ipsilateral anterograde corticospinal tract tracing with biotinylated dextran amine (BDA) showed that HI reduced BDA labeling of the contralateral spinal cord. Only MSC-3+10 treatment partially restored contralateral spinal cord BDA staining, indicating enhanced axonal remodeling. MSC-3 enhanced formation of bromodeoxyuridine-positive neurons and oligodendrocytes. Interestingly, the second gift at day 10 did not further increase new cell formation, whereas only MSC-10 d

Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage.

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ.

Laboratory for Neuroimmunology and Developmental Origins of Disease [C.T.J.V., A.K., C.J.H.;, Department of Neonatology [C.T.J.V., F.B.], University Medical Center Utrecht,, 3584 EA Utrecht,, The Netherlands.

Abstract

Mesenchymal stem cell (MSC) transplantation is a promising therapy to regenerate the brain after an ischemic event. We investigated the possibility to use the nasal route as a non-invasive method to repair the neonatal damaged brain. Nine-day old mice underwent cerebral hypoxia-ischemia (HI) and MSC were transplanted intranasally 10 days after HI. At 28 days after HI, MSC were still present in the affected hemisphere, but had not differentiated into cerebral cell types. Intranasal MSC-treatment significantly improved sensorimotor function in the cylinder rearing test at 21 and 28 days after HI. Furthermore, intranasal MSC-treatment decreased grey and white matter area loss when determined 28 days after HI by 34% and 37% respectively. MSC cultured in vitro with brain extracts obtained 10 days after HI, responded to the ischemic brain by upregulation of several growth factors, including FGF2 and NGF in comparison to brain extracts of sham-operated controls. In conclusion, MSC can reliably be delivered to the brain via the nasal route to induce functional recovery as well as a reduction in brain lesion size. We propose that MSC function by stimulating endogenous cerebral repair by adapting their secretion profile to the ischemic brain leading to upregulation of repair promoting factors. ABBREVIATIONS::

PMID: 20639794 [PubMed - as supplied by publisher]

id. These findings indicate that increased positive effect of MSC-3+10 compared with MSC-3 alone is mediated via distinct pathways. We hypothesize that MSCs adapt their growth and differentiation factor production to the needs of the environment at the time of intracranial injection. Comparing the response of MSCs to in vitro culture with HI brain extracts obtained at day 10 from MSC-3- or vehicle-treated animals by pathway-focused PCR array analysis revealed that 29 genes encoding secreted factors were indeed differentially regulated. We propose that the function of MSCs is dictated by adaptive specific signals provided by the damaged and regenerating brain.

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