Migration of bone marrow stem cells in ischaemic brain W. S. Poon

Acta Neurochir Suppl (2006) 99: 123–124

# Springer-Verlag 2006 Printed in Austria

Migration of bone marrow stem cells in ischaemic brain

W. S. Poon ¹ , G. Lu ^{1 ;3} , K. S. Tsang ² , X. L. Zhu ¹ , G. G. Chen ¹ , and H. K. Ng ²

1

Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong

2

Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong

3

Department of Neurosurgery, Kun Ming Medical College, Yun Nan, China

Summary

Stem cell therapy has been demonstrated to be effective in the man- agement of haematological malignancy and solid cancer, but its role in neurodegenerative conditions remains uncertain. We hypothesize that:

(1) ventricular delivery of bone marrow stem cells improves functional outcome in experimental ischaemia of the mouse brain; and (2) this improved outcome is due to migration of bone marrow stem cells to areas of ischaemia. Twelve mice with transient cerebral hemisphere ischaemia were randomly allocated to receive bone marrow stem cells or saline. The six animals that underwent cell therapy were found to perform better and committed fewer errors in the water maze system compared with the six control mice. Migration of these bone marrow stem cells was evident within the ventricular cerebro-spinal fluid (CSF) system and the brain parenchyma. This could also occur in clusters of cells. Preferential migration of these cells took place in lesioned areas.

Keywords: Bone marrow stem cells; cerebral ischaemia; water maze system.

Introduction

Stem cell therapy is generally regarded as a potential treatment modality for cancer and degenerative diseases.

In neurodegenerative disorders such as stroke, spinal cord injury, Parkinson’s disease and Alzheimer disease [5], consistent efficacy and its biological mechanism have not been worked out. In this study, two questions were asked: (1) Could the impaired learning and mem- ory ability of the mice with transient cerebral ischaemia be improved by stem cell therapy ? (2) If so, does mi- gration of the stem cells into areas of cerebral ischae- mia occur ?

Material and methods

Twelve mice were selected for the experiment, where it took them approximately 90 seconds to pass the spatial learning and memory

test using the water maze system after training [1, 6]. Cerebral hemi- sphere ischaemia was induced by a 20-minute occlusion of both common carotid arteries [2, 4]. Ten micro liter of 2.5 10

bone marrow-derived stem cells, labelled with bromodeoxyuridine (BrdU), were injected stereotactically into the right lateral ventricle of the mouse brain one day after ischaemia induction. Behavioural assess- ment of the ischaemic mice four weeks post-transplant was per- formed using the water maze system for five days. Animals were then euthanized. After reperfusion with paraformaldehyde, the brain was removed. Immunostaining of BrdU and NeuN were performed in frozen sections of 10 mm thickness.

Results

Compared with the control mice having sham opera- tions, the time taken for completion of the behavioural assessment was significantly shorter (mean  1 standard deviation: 29  10s vs 45  13s; p ¼ 0.01) and the inci- dence of errors committed on day five by ischaemic mice with undergone cellular therapy was significantly reduced (2  1 vs 6  2; p ¼ 0.001). BrdU-labeled bone marrow stem cells were noted to migrate from the ven- tricular CSF system to the brain parenchyma (Fig. 1).

Migration of BrdU ^þ cells in clusters was also demon- strated in the lesioned brain where loss of neurons was demonstrated (Fig. 2).

Discussion =conclusion

Migration of implanted bone marrow stem cells occurs in an orderly and systematic fashion. The co-adhesion of the implanted cells led to cell clusters migrating to le- sioned areas. These phenomena may be attributable to the micro-environment provided by the cerebral ischaemia.

The development of successful cell therapy strategies for

brain repair requires the elucidation of this ill-understood regulatory mechanism in the nervous system [3].

References

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4. Terashima T, Namura S, Hoshimaru M, Uemura Y, Kikuchi H, Hashimoto N (1998) Consistent injury in the striatum of C57BL =6 mice after transient bilateral common carotid artery occlusion.

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183–193

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Correspondence: Wai S. Poon, Prince of Wales Hospital, Shatin, Hong Kong. e-mail: wpoon@surgery.cuhk.edu.hk

Fig. 1. Migration of implanted bone marrow stem cells to the parenchyma of the ventricular system. (A) H&E-stained brain section (B, C and D) migration of BrdU-labelled bone marrow stem cells to the highlighted area

Fig. 2. Implantation of cell clusters to the lesioned area of the cortex

124 W. S. Poon et al.: Migration of bone marrow stem cells in ischaemic brain