CNS Plasticity of Human Adipo-derived Multipotent Cells

描述（由申请人提供）： 干细胞和再生细胞疗法在治疗各种疾病方面有很大的前景;然而，将这种前景转化为临床领域的最佳细胞来源仍有待确定。胚胎干细胞的使用充满了伦理和政治争议，这些细胞提出了几个实际问题，包括供应充足和非自体组织反应。成体干细胞提供了一个争议较少的，可能是自体的解决方案，但其效用可能受到发育可塑性有限和供应不足的限制。理想的细胞来源应该是丰富的、可消耗的、可再生的、自体的，并且应该容易和安全地收获。这些细胞应该具有相当大的生长能力，发育可塑性，理想情况下不受道德和政治约束。最近，我们已经证明了在人类皮下脂肪组织中存在多能细胞。这些细胞具有广泛生长、更新的能力，并且可以在体外沿着外胚层和中胚层来源的谱系分化。此外，脂肪组织是一种丰富的自体细胞来源，可以轻松安全地获取。在这项R21申请中提出的研究将研究成年人脂肪来源的细胞（hADC）在大鼠中枢神经系统中的可塑性，hADC能够在体外分化为具有神经表型的细胞。初步研究结果表明，hADC在注射到脑中后存活，在幼稚和损伤（缺血后）脑中长距离迁移，表现出靶向迁移到损伤区域，并在体内存活至少10周（迄今为止测试的最长时间）。本申请的中心假设是hADC可以在中枢神经系统中移植和迁移，表现出靶向迁移到脑损伤区域，分化成神经细胞类型，并表现出长期存活。这一假设将在两个具体目标的背景下进行评估。目的1将鉴定植入幼稚（即未损伤）大鼠CNS中的hADC的表型和位置命运。目的2：研究hADCs在大鼠中枢神经系统短暂缺血后的表型和位置变化。这些研究的结果将提供大脑中hADC可塑性的第一个证据，并可能为未来CNS中基于细胞的治疗奠定基础。

DESCRIPTION (provided by applicant): Stem cells and regenerative cell therapies hold great promise for treating a variety of disorders; however, an optimal cell source for translating this promise into the clinical realm remains to be determined. The use of embryonic stem cells is fraught with ethical and political controversy, and these cells present several practical issues, including adequacy of supply and non-autologous tissue responses. Adult stem cells offer a less controversial, and potentially autologous, solution; but their utility may be restricted by a limited range of developmental plasticity and an inadequacy of supply. An ideal source of cells would be abundant, expendable, replenishable, autologous, and should be easy and safe to harvest. The cells should possess considerable growth capacity, developmental plasticity, and ideally would be free of ethical and political constraints. Recently, we have demonstrated the existence of multipotent cells within human subcutaneous adipose tissue. These cells have the capacity for extensive growth, renewal, and can differentiate in vitro along ectodermally and mesodermally derived lineages. Moreover, adipose tissue represents an abundant, autologous source of cells, which can be easily and safely harvested. The studies proposed in this R21 application will investigate the plasticity of adult human adipo-derived cells (hADCs) in the rat central nervous system, hADCs are capable of differentiating into cells with neural phenotypes in vitro. Preliminary findings indicate that hADCs survive injection into the brain, migrate long distances in naive and injured (post-ischemic) brains, exhibit targeted migration to regions of injury, and survive for at least 10 weeks in vivo (the longest period tested to date). The central hypothesis of this application is that hADCs can engraft and migrate in the central nervous system, exhibit targeted migration to areas of cerebral injury, differentiate into neural cell types, and exhibit long-term survival. This hypothesis will be evaluated in the context of two specific aims. Aim 1 will identify the phenotypic and positional fates of hADCs implanted into the CNS of naive (i.e. uninjured) rats. Aim 2 will identify the phenotypic and positional fates of hADCs implanted into rat CNS after injurious transient ischemia. The results of these studies will provide the first evidence of hADC plasticity in the brain and could form the foundation for future cell-based therapies in the CNS.