Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats
Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats
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DOI：
10.1073/pnas.0808488105
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发表时间：
2008-10-28
影响因子：
11.1
通讯作者：
Perrier, Anselme L.
中科院分区：
文献类型：
--
作者：
Aubry, Laetitia;Bugi, Aurore;Perrier, Anselme L.
使用胎儿纹状体移植物的替代细胞疗法在亨廷顿病患者中已初步显示出临床成功，但获取胎儿细胞所需的物流条件阻碍了其在相关患者群体中的推广。人类胚胎干细胞（hES细胞）理论上可以应对这一挑战，因为它们可以无限增殖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。这种hES衍生细胞在异种移植到成年大鼠体内后可分化为纹状体神经元，这进一步证实了其治疗潜力。我们的研究结果为亨廷顿病的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大脑中的异种移植物过度生长，这表明走向临床应用需要一种在移植后使其停止增殖的方法。
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.