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Bone Marrow Stromal Cells Promote Neurite Extension in Organotypic Spinal Cord Slice: Significance for Cell Transplantation Therapy

Department of Neurosurgery Hokkaido University Graduate School of Medicine, hshichi{at}med.hokudai.ac.jp

Satoshi Kuroda, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Sachiko Tsuji, MD, PhD

Department of Neurology Hokkaido University Graduate School of Medicine, Hokkaido, Japan

Satoshi Yamaguchi, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Shunsuke Yano, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Jang-Bo Lee, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Hiroyuki Kobayashi, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Seiji Kikuchi, MD, PhD

Department of Neurology Hokkaido University Graduate School of Medicine, Hokkaido, Japan

Kazutoshi Hida, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Yoshinobu Iwasaki, MD, PhD

Department of Neurosurgery Hokkaido University Graduate School of Medicine

Objective. Recent reports have indicated that bone marrow stromal cells (BMSCs) have the potential to improve neurological function when transplanted into models of central nervous system (CNS) disorders, including traumatic spinal cord injury. In this study, the authors aimed to clarify the underlying mechanism through which BMSCs supported CNS regeneration in the spinal cord. Methods. The authors topically applied mouse BMSCs expressing green fluorescence protein (0.4-4 x 10⁴ cells) on the organotypic spinal cord slice culture prepared from 6-day-old rat pups (n = 17). They were co-cultured for 3 weeks after the slice culture started, and the behavior of the applied BMSCs was serially observed using a fluorescence bioimaging technique. The authors completed a histological analysis at the end of the co-cultures and evaluated the profiles of the cultured BMSCs using microarray and immunocytochemistry techniques. Results. The fluorescence bioimaging showed that the BMSCs survived and made a cluster on the slice during the experiments. They also induced a morphological change in the slice within 48 hours of co-culture. Immunohistochemistry analysis showed that the BMSCs promoted a marked neurite extension toward their cluster and some of the BMSCs expressed Tuj-1, an early neuronal marker. Analysis by microarray and immunocytochemistry revealed that BMSCs highly expressed the matrix metalloproteinases (MMPs), stromal cell—derived factor-1, and its specific receptor CXCR4. Conclusions . These findings suggest that the donor BMSCs can support CNS regeneration due to their acquisition of a suitable environment for differentiation and promotion of neurite extension via MMPs and chemokines.

Key Words: Bone marrow stromal cell • Organotypic spinal cord slice culture • Neurite extension • Neuronal regeneration • Cell transplantation.

Neurorehabilitation and Neural Repair, Vol. 22, No. 5, 447-457 (2008)
DOI: 10.1177/1545968308315596


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