Intracerebral transplantation of bone marrow with BDNF after MCAo in rat
Introduction
Neurotransplantation has been used to investigate development, plasticity and regeneration of the central nervous system (Boyer and Bakay, 1995). Transplanted embryonic cells may aid in the restoration of lost function by contributing trophic support or integrating into functional synaptic networks with host tissues. Experimental animal models and human trials show great promise in this regard (Kordower et al., 1995; Defer et al., 1996; Borlongan et al., 1998). However, numerous ethical and logistical problems make it unlikely that human fetal tissue will be readily available in sufficient quantity to serve as a practical and immediate source for therapeutic transplants. For these reasons, alternative graft sources have been explored such as encapsulated and genetically engineered cells, fibroblasts, fetal astrocytes (Andersson et al., 1993) and Sertoli cells (Sanberg et al., 1997).
Adult bone marrow (BM) contains stem and progenitor cells that have multiple differentiation potentials (Prockop, 1997), and can differentiate into both microglia and macroglia in the brain of adult mice (Eglitis and Mezey, 1997). BM cells also contain a substantial amount of catecholamines and they are capable of secreting neurochemicals (Maestroni et al., 1998). Thus, bone marrow stem cells appear to have a wide differentiation potential.
The administration of brain-derived neurotrophic factor (BDNF) to the intact adult rat brain is associated with significant behavioral and neurochemical alterations (Altar et al., 1992; Martin-Iverson et al., 1994). Intraventricular administration of BDNF reduces infarct size after focal cerebral ischemia in rats and supports the hypothesis of a neuroprotective role for BDNF in stroke (Schabitz et al., 1997). The current investigation was designed to test the hypothesis that a composite graft of fresh adult bone marrow and BDNF results in superior grafting and improved functional recovery after middle cerebral artery occlusion (MCAo) in rats.
Section snippets
Materials and methods
All experimental procedures were approved by the Care of Experimental Animals Committee of Henry Ford Hospital.
Results
Within 6 γm thick coronal sections stained with H&E, dark and red neurons were observed in the ischemic core of all rats subjected to MCAo with and without donor transplantation. No significantly reduced volume of ischemic damage was detected in rats with any donor treatment, compared with control rats subjected to MCAo with or without PBS (Table 1). A nearly complete loss of parenchymal cell immunoreactivity (NeuN, GFAP) in the ischemic core was observed at 7 days after MCAo. However, the IBZ of
Discussion
We have shown that intracerebral transplantation of a combination of BM with BDNF is effective in enhancing behavioral recovery in the motor and somatosensory tests 7 days after MCAo in rats. The present observation that grafts of BM with BDNF promoted the amelioration of ischemic-induced behavioral deficits in rats is consistent with earlier reports showing that grafting of fetal striatal cells into the caudatoputamen partially restores functions impaired by ischemia-induced damage in the
Acknowledgements
The authors wish to thank Cecylia Powers, Cynthia Roberts and Xiuli Zhang for technical assistance, and Denice Bliesath for secretarial support. This work was supported by NINDS grants PO1 NS23393 and RO1 NS35504.
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