Neuroscience Department, University of the Basque Country UPV/EHU, IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
PLoS One. 2010 Dec 30;5(12):e15914. doi: 10.1371/journal.pone.0015914.
Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.
With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery.
Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.
脊髓损伤（SCI）是一种广泛传播的疾病，目前对任何症状都没有有效的治疗方法。通过细胞移植进行再生医学是一种非常有吸引力的策略，可以通过不同的非排他性方式用于促进功能恢复。我们研究了在脊髓损伤大鼠中移植人胚胎神经祖细胞（hENP）后的功能和结构结果。
为了将其转化为临床，我们选择了延迟移植的范例，即在成年大鼠严重脊髓压迫模型中，损伤后一周进行移植。hENP 要么是未修饰的，要么是表达 Neurogenin 2（Ngn2）的工程细胞。此外，我们比较了整合和非整合的慢病毒载体，因为后者具有较低的插入突变风险。我们发现，表达 Ngn2 的 hENP 移植完全恢复了体重支持，并改善了严重胸段脊髓压迫后的运动功能恢复。这与 5-羟色胺能神经支配在腰段的部分恢复以及 5-HT1A 受体向运动神经元质膜的易位有关。由于 hENP 在移植后 4 周内无法检测到，因此 Ngn2 的短暂表达足以实现运动恢复并允许轴突再生。重要的是，我们还证明移植未修饰的 hENP 对功能恢复有害。
表达 Ngn2 的 hENP 的移植和短期存活可恢复 SCI 后的体重支持，并部分恢复损伤以下的 5-羟色胺纤维密度和 5-HT1A 受体模式。此外，与仅损伤动物相比，移植未修饰的 hENP 被发现会导致结果恶化，因此指出了干细胞治疗本身在 SCI 中的潜在有害影响。考虑到越来越多的涉及 SCI 患者的细胞移植临床试验，这一点非常重要。
