Elsevier

Neuropharmacology

Volume 39, Issue 5, April 2000, Pages 711-716
Neuropharmacology

Intracerebral transplantation of bone marrow with BDNF after MCAo in rat

https://doi.org/10.1016/S0028-3908(00)00006-XGet rights and content

Abstract

We tested the hypothesis that a composite graft of fresh bone marrow (BM) along with brain-derived neurotrophic factor (BDNF), transplanted into the ischemic boundary zone (IBZ) of rat brain, facilitates BM cells to survive and differentiate, and improves functional recovery after middle cerebral artery occlusion (MCAo). The fresh BM was harvested from adult rats injected with bromodeoxyuridine (BrdU) as a tracer. Rats (n=37) were subjected to 2 h of MCAo, received grafts at 24 h and were sacrificed at 7 days after MCAo. Test groups consisted of: (1) control — MCAo alone (n=9); (2) injection of phosphate buffered saline (n=4); (3) transplantation of BM (n=8); (4) injection of BDNF (n=7); and (5) transplantation of BM with BDNF (n=9) into the IBZ. Immunohistochemistry was used to identify cells derived from the BM stem cells. Behavioral tests (rotarod motor test; adhesive-removal somatosensory test) were performed before and 7 days after MCAo. The data indicate that intracerebral grafting of a combination of BM with BDNF enhances differentiation of BM cells and significantly improves motor recovery of rotarod (P<0.05) and adhesive-removal (P<0.05) tests. We anticipate that BM along with neurotrophic factors may provide a powerful autoplastic therapy for human neurological injury and degenerative disorders.

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.

References (36)

  • C. Peters et al.

    Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome

    Blood

    (1996)
  • H. Sauer et al.

    Brain-derived neurotrophic factor enhances function rather than survival of intrastriatal dopamine cell-rich grafts

    Brain Research

    (1993)
  • T. Schallert et al.

    Recovery of function after brain damage: severe and chronic disruption by diazepam

    Brain Research

    (1986)
  • R. Timpl

    Macromolecular organization of basement membranes

    Current Opinion in Cell Biology

    (1996)
  • K.S. Zuckerman et al.

    Extracellular matrix production by the adherent cells of long-term murine bone marrow cultures

    Blood

    (1983)
  • S. Ahmed et al.

    BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors

    Journal of Neuroscience

    (1995)
  • J.A. Allay et al.

    LacZ and interleukin-3 expression in vivo after retroviral transduction of marrow-derived human osteogenic mesenchymal progenitors

    Human Gene Therapy

    (1997)
  • C.A. Altar et al.

    Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo

    Proceedings of the National Academy of Science, USA

    (1993)
  • Cited by (175)

    • Post-stroke treatment of storax improves long-term outcomes of stroke in rats

      2021, Journal of Ethnopharmacology
      Citation Excerpt :

      All rats were trained 3 days before the stroke and tested once a day to ensure that the animals were able to remove the adhesive sticker. The time required for each animal was the average of 4 trials (Chen et al., 2000; Schallert et al., 1986). Foot-fault test — The foot-fault test was carried out to evaluate sensorimotor function.

    • Formononetin recovered injured nerve functions by enhancing synaptic plasticity in ischemic stroke rats

      2020, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      The higher the score, the more serious the defect. The rotarod test was performed as described above [18,19]. Briefly, rats were placed on a rotating drum with a speed slowly increasing from 4 to 40 rpm within 5 min.

    View all citing articles on Scopus
    View full text