Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy.
We developed human mesenchymal stem cell (MSC) lines that could differentiate into various tissue cells including bone, neural cells, bone marrow (BM) stromal cells supporting the growth of hematopoietic stem cell (HSC), and so-called 'tumor stromal cells' mixing with tumor cells. We investigated the applicability of MSC as therapeutic cell transplanting reagents (cytoreagents). Telomerized human BM derived stromal cells exhibited a prolonged lifespan and supported the growth of hematopoietic clonogenic cells. The gene transfer of Indian hedgehog (Ihh) remarkably enhanced the HSC expansion supported by the human BM stromal cells. Gene-modified MSC are useful as therapeutic tools for brain tissue damage (e.g. brain infarction) and malignant brain neoplasms. MSC transplantation protected the brain tissue from acute ischemic damage in the midcerebral artery occlusion (MCAO) animal model. Brain-derived neurotrophic factor (BDNF)-gene transduction further enhanced the protective efficacy against the ischemic damage. MSC possessed excellent migratory ability and exerted inhibitory effects on the proliferation of glioma cells. Gene-modification of MSC with therapeutic cytokines clearly augmented the antitumor effect and prolonged the survival of tumor-bearing animals. Gene therapy employing MSC as a tissue-protecting and targeting cytoreagent would be a promising approach.
Hamada
Hirofumi
H
Department of Molecular Medicine, Sapporo Medical University, Sapporo 060-8556, Japan. hhamada@sapmed.ac.jp
Kobune
Masayoshi
M
Nakamura
Kiminori
K
Kawano
Yutaka
Y
Kato
Kazunori
K
Honmou
Osamu
O
Houkin
Kiyohiro
K
Matsunaga
Takuya
T
Niitsu
Yoshiro
Y
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology; D002545:Brain Ischemia / Q000628:therapy; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy; D002454:Cell Differentiation; D002470:Cell Survival; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000628:therapy; D053823:Hedgehog Proteins; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D019098:Telomerase / Q000235:genetics / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D019098:Telomerase