Autocrine Production of IGF-I Increases Stem Cell-Mediated Neuroprotection
Autocrine Production of IGF-I Increases Stem Cell-Mediated Neuroprotection
复制标题
DOI：
10.1002/stem.1933
复制
发表时间：
2015-05-01
期刊：
影响因子：
5.2
通讯作者：
Feldman, Eva L.
中科院分区：
文献类型：
--
作者：
Lunn, J. Simon;Sakowski, Stacey A.;Feldman, Eva L.
肌萎缩侧索硬化症（ALS）是一种导致运动神经元（MN）丧失的致命性神经退行性疾病。目前还没有有效的治疗方法;然而，使用神经祖细胞的细胞疗法可以保护MN并减缓G93 A-SOD 1 ALS大鼠的疾病进展。最近，我们完成了一项I期临床试验，研究了ALS患者的椎管内人类脊髓干细胞（HSSC）移植，证明了我们的方法是安全可行的，支持了目前正在进行的II期试验。同时，致力于了解HSSC在体外和ALS动物模型中临床前益处的机制，使我们研究胰岛素样生长因子-I（IGF-I）的产生如何有助于细胞治疗神经保护。IGF-I是一种有效的生长因子，在临床前ALS研究中已证实有效，我们认为自分泌IGF-I的产生可能会增强HSSC的有益作用。通过比较HSSCs的生物学特性，HSSCs表达六倍高水平的IGF-I，我们证明，IGF-I的生产增加了胶质源性神经营养因子的生产，并加速轴突生长，而不会对HSSC增殖或终末分化产生不利影响。此外，我们证明，增加IGF-I诱导更有效的MN保护兴奋性毒性通过间接和直接的机制，如使用悬挂插入与初级MN或培养器官型脊髓切片，分别证明。这些发现支持了我们的理论，即自分泌生长因子的产生与HSSC移植相结合，可能提供一种新的手段，以实现附加的ALS神经保护。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93A-SOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulin-like growth factor-I (IGF-I) production contributes to cellular therapy neuroprotection. IGF-I is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGF-I production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGF-I, we demonstrate that IGF-I production augments the production of glial-derived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGF-I induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS.