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The rapid progress in stem cell research has provided several tissue sources such as embryonic stem cells, induced pluripotent stem cells or mesenchymal stem cells that can provide tissue for restaurative therapies of brain disorders. However, clinical transplantations using such tissue have been sparse. The first FDA approved clinical applications of stem or progenitor cells to the brain employed human neural progenitor cells (hNPCs). These cells may be relatively safe since there has been no tumor formation in animal experiments and no serious adverse events in the above mentioned clinical studies. On the other hand, pluripotency and self renewal may be limited in progenitor cells derived from the fetal or adult human brain. Previous reports raised concerns in respect to early senescence and chromosomal instability.Our goal was to improve stability of tissue specific fetal hNPCs with a special focus on midbrain derived cells and their conversion into dopaminergic neurons. We were able to demonstrate that low oxygen is critical for long term expansion triggering hypoxia inducible factor 1 alpha dependent and independent mechanisms. Detailed analyses show, that hNPCs remain surprisingly stable at least during the first 20 passages. Growth curves remain stable and indicate that appr. 1017 hNPCs can be generated from a single specimen over 200 days in culture. During proliferation, there is a rapid wash out of glial (GFAP, O4) and neuronal markers (Tuj1, TH, DAT) but an increase of markers for pluripotency (nestin, CD15, CD133, CD184) and cell cycle (Ki67, PCNA). Following differentiation appr. 30 – 50% of these cells convert into cells expressing neuronal markers and midbrain derived tissue gives rise to up to 20 % of cells expressing tyrosine hydroxylase. These cells release dopamine and improve motor behavior in unilateral 6-hydroxydopamine rat or primate models of Parkinson’s disease. No chromosomal abnormalities were found following long-term expansion.In addition, we have also been able to expand NPCs from fetal human striatal or spinal cord tissue for generation of medium spiny neurons or motor neurons. We hope that such cells will be relevant to better understand or treat Huntington’s disease or spinal cord lesions. We provide evidence that hNPCs can be readily expanded and that these cells preserve the potential to differentiate into functional (dopaminergic) neurons without increasing their teratogenic potential, thus fetal hNPC’s are an alternative cell source to study human brain development and search for novel therapies.

저자

• Johannes SCHWARZ [ Department of Neurology,University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany. ]

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간행물

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• 간행물명

  한국생물공학회 학술대회

• 간기

  반년간

• 수록기간

  1985~2013

• 십진분류

  KDC 476 DDC 576