Bone Marrow Stem Cell Grafts For Neurogenic Pain

骨髓干细胞移植治疗神经源性疼痛

• 批准号: 7048677
• 负责人: Jacqueline Sagen
• 金额: $ 17.11万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-05 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048677
• 关键词: analgesia; bone marrow transplantation; chronic pain; dorsal horn; enkephalins; human tissue; injection /infusion; laboratory rat; nonhuman therapy evaluation; pain threshold; peripheral nervous system; spinal cord injury; stem cell transplantation; tissue /cell culture; tissue engineering

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.

描述（由申请人提供）：由神经系统损伤引起的神经源性疼痛通常是持续性的和使人衰弱的，并且由于其对传统疗法的反应不佳而呈现出显著的临床挑战。已经探索了使用细胞移植到脊髓中的新的干预策略，以提供镇痛剂和神经营养因子的局部和持续可再生的来源，或替代丢失的细胞群。然而，由于人类器官供体可用性、免疫原性和潜在疾病传播的限制，选择合适的细胞用于移植是具有挑战性的。这项R21探索性资助提案的目标是评估使用自体干细胞样骨髓细胞作为载体将镇痛剂递送至局部脊柱部位以缓解神经源性疼痛的可行性。使用可以离体扩增的自体细胞将克服与其他供体来源相关的限制，以及围绕使用胚胎干细胞的潜在伦理异议。此外，骨髓基质细胞已被证明在静脉注射时选择性地迁移并“回家”到CMS的受损区域，因此可以提供微创移植方法。为了评价该方法治疗外周或中枢损伤所致疼痛的效果，将使用一种独特的人骨髓基质细胞亚群，该细胞已显示出胚胎干细胞自我更新和分化特性（称为骨髓分离的成体多谱系诱导细胞或迈阿密细胞）。将静脉内或鞘内施用细胞，并使用两种不同的神经源性疼痛模型评估其靶向脊髓和递送镇痛剂的能力：用于兴奋性毒性脊髓损伤疼痛的使君子酸（QUIS）模型和用于外周神经性疼痛的慢性压迫性损伤（CCI）模型。第一种产生与背角中明显的神经元损失相关的相当大的病变部位，而第二种在背角中产生更微妙的病理和重组，两者都导致异常疼痛处理，包括异常性疼痛、痛觉过敏和感觉迟钝。提出了两个具体的目标;第一个是评估迈阿密细胞在QUIS或CCI后回到背角病理部位的能力，第二个是评估潜在的细胞介导的镇痛剂递送到这些部位的能力，使用经工程改造产生脑啡肽原的细胞作为概念证明。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改变。如果成功的话，这些研究的结果应该会导致慢性神经源性疼痛管理的新的和有效的策略的发展。

项目成果

Sustained analgesic peptide secretion and cell labeling using a novel genetic modification.

使用新型基因修饰持续镇痛肽分泌和细胞标记。

• 发表时间: 2008
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Gajavelli,Shyam;Castellanos,DanielA;Furmanski,Orion;Schiller,PaulC;Sagen,Jacqueline
• 通讯作者: Sagen,Jacqueline