Aubry Laetitia, Bugi Aurore, Lefort Nathalie, Rousseau France, Peschanski Marc, Perrier Anselme L
Institut National de la Santé et de la Recherche Médicale/Université d'Evry-Val-d'Essonne Unité Mixte de Recherche 861, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Association Française contre les Myopathies, 91030 Evry, France.
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16707-12. doi: 10.1073/pnas.0808488105. Epub 2008 Oct 15.
Substitutive cell therapy using fetal striatal grafts has demonstrated preliminary clinical success in patients with Huntington's disease, but the logistics required for accessing fetal cells preclude its extension to the relevant population of patients. Human embryonic stem (hES) cells theoretically meet this challenge, because they can be expanded indefinitely and differentiated into any cell type. We have designed an in vitro protocol combining substrates, media, and cytokines to push hES cells along the neural lineage, up to postmitotic neurons expressing striatal markers. The therapeutic potential of such hES-derived cells was further substantiated by their in vivo differentiation into striatal neurons following xenotransplantation into adult rats. Our results open the way toward hES cell therapy for Huntington's disease. Long-term proliferation of human neural progenitors leads, however, to xenograft overgrowth in the rat brain, suggesting that the path to the clinic requires a way to switch them off after grafting.
使用胎儿纹状体移植的替代细胞疗法已在亨廷顿舞蹈症患者身上取得了初步临床成功，但获取胎儿细胞所需的后勤工作使其无法推广至相关患者群体。人类胚胎干细胞（hES）理论上可以应对这一挑战，因为它们可以无限扩增并分化为任何细胞类型。我们设计了一种体外方案，结合底物、培养基和细胞因子，促使hES细胞沿着神经谱系分化，直至分化为表达纹状体标志物的有丝分裂后神经元。将这些hES来源的细胞异种移植到成年大鼠体内后，它们在体内分化为纹状体神经元，进一步证实了此类细胞的治疗潜力。我们的研究结果为亨廷顿舞蹈症的hES细胞疗法开辟了道路。然而，人类神经祖细胞的长期增殖会导致大鼠脑内异种移植物过度生长，这表明通往临床应用的道路需要找到一种在移植后使其停止生长的方法。
