Bone Marrow Stem Cell Grafts For Neurogenic Pain

描述(申请人提供)：神经系统损伤引起的神经源性疼痛通常是持续性和衰弱的，并提出了一个重大的临床挑战，因为它对传统的治疗方法没有很好的反应。使用细胞移植到脊髓中的新的干预策略已经被探索，以提供局部的和持续可再生的止痛剂和神经营养因子的来源，或者取代丢失的细胞群。然而，由于人类器官供体的可获得性、免疫原性和潜在的疾病传播能力的限制，为移植选择合适的细胞是具有挑战性的。这项R21探索性资助计划的目的是评估使用自体干细胞样骨髓细胞作为载体将止痛剂输送到局部脊髓部位以减轻神经源性疼痛的可行性。使用可在体外扩增的自体细胞将克服与其他捐赠者来源相关的限制，以及围绕使用胚胎干细胞的潜在伦理反对。此外，当静脉注射时，骨髓基质细胞可以选择性地迁移到CMS的受损区域，因此可能提供一种微创的移植方法。为了评估这种治疗外周或中枢损伤引起的疼痛的方法，将使用一组独特的人骨髓基质细胞亚群，这些细胞已被证明具有胚胎干细胞的自我更新和分化特性(称为骨髓分离成人多系诱导细胞或迈阿密细胞)。细胞将被静脉或鞘内注射，并使用两种不同的神经源性疼痛模型来评估其靶向脊髓和输送止痛药的能力：用于兴奋性脊髓损伤疼痛的Quis模型和用于周围神经病理性疼痛的慢性收缩损伤(CCI)模型。前者产生相当大的病变部位，与背角明显的神经元丢失有关，而后者产生更微妙的病理和背角重组，两者都导致异常的疼痛处理，包括痛觉异常、痛觉过敏和感觉障碍。提出了两个具体的目标：第一个评估迈阿密细胞在QUIS或CCI后定位后角病理部位的能力，第二个评估潜在的细胞介导的止痛剂输送到这些部位，使用工程细胞产生前脑啡肽作为概念的证明。评估将包括疼痛行为、宿主-移植物整合、脊髓神经化学和潜在病理学的变化。如果成功，这些研究的结果应该会导致开发新的和有效的策略来管理慢性神经源性疼痛。

DESCRIPTION (provided by applicant): Neurogenic pain resulting from injury to the nervous system is often persistent and debilitating, and presents a significant clinical challenge as it does not respond well to traditional therapies. Novel interventive strategies using cellular transplantation into the spinal cord have been explored to provide a local and continually renewable source of analgesic agents and neurotrophic factors or to replace lost cellular populations. However, the selection of appropriate cells for transplantation is challenging, due to limitations in human organ donor availability, immunogenicity, and potential disease transmission. The goal of this R21 Exploratory grant proposal is to evaluate the feasibility of using autologous stem cell-like bone marrow cells as vehicles for delivering analgesic agents to local spinal sites for alleviation of neurogenic pain. The use of autologous cells that can be expanded ex vivo would overcome the limitations associated with other donor sources, as well as the potential ethical objections surrounding the use of embryonic stem cells. In addition, bone marrow stromal cells have been shown to migrate selectively and "home" to damaged regions of the CMS when injected intravenously, and thus may offer a minimally invasive grafting approach. In order to evaluate this approach for pain due to peripheral or central injury, a unique subpopulation of human bone marrow stromal cells which have been shown to exhibit embryonic stem cell self-renewal and differentiation properties (named the Marrow-Isolated Adult Multilineage Inducible or MIAMI cells), will be used. Cells will be administered intravenously or intrathecally and assessed for their ability to target the spinal cord and to deliver analgesic agents using two distinct models of neurogenic pain: the quisqualic acid (QUIS) model for excitotoxic spinal cord injury pain and the chronic constriction injury (CCI) model for peripheral neuropathic pain. The first produces a fairly large lesion site associated with overt neuronal loss in the dorsal horn, while the second produces a more subtle pathology and reorganization in the dorsal horn, both resulting in abnormal pain processing including allodynia, hyperalgesia, and dysesthesias. Two specific aims are proposed; the first to evaluate the ability of the MIAMI cells to home to sites of pathology in the dorsal horn following QUIS or CCI, and the second to evaluate potential cell-mediated delivery of analgesic agents to these sites using cells engineered to produce proenkephalin as a proof of concept. Evaluations will include alterations in pain behaviors, host-graft integration, spinal neurochemistry, and potential pathology. If successful, findings from these studies should lead to development of novel and potent strategies in the management of chronic neurogenic pain.