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大有可为；然而，将这一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，这些细胞存在几个实际问题，包括供应充足和非自体组织反应。成体干细胞提供了一种争议性较小且可能是自体的解决方案；但它们的用途可能受到发育可塑性范围有限和供应不足的限制。理想的细胞来源应该是丰富的、可消耗性的、可补充的、自体的，并且应该容易和安全地采集。细胞应该具有相当大的生长能力、发育可塑性，理想情况下不受伦理和政治限制。最近，我们证实了人类皮下脂肪组织中存在多能细胞。这些细胞具有广泛的生长、更新能力，并能沿着外胚层和中胚层来源的谱系在体外分化。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。这项R21应用中提出的研究将探讨成年人类脂肪来源细胞(HADC)在大鼠中枢神经系统中的可塑性，hADC在体外能够分化为具有神经表型的细胞。初步研究结果表明，hADC注射入脑后存活，在幼稚和受损(缺血后)脑中长距离迁移，有针对性地迁移到损伤区域，并在体内存活至少10周(迄今为止测试的最长时间)。这一应用的中心假设是hADC可以在中枢神经系统中移植和迁移，表现出向脑损伤区域的靶向迁移，分化为神经细胞类型，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鉴定hADC植入幼年(即未损伤)大鼠中枢神经系统的表型和定位命运。目的2鉴定hADC在损伤性短暂性脑缺血后植入大鼠中枢神经系统的表型和定位命运。这些研究的结果将为hADC在大脑中的可塑性提供第一个证据，并可能为未来中枢神经系统的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.