Regenerating CNS white matter using induced pluripotent stem cells

使用诱导多能干细胞再生中枢神经系统白质

• 批准号: 9077989
• 负责人: Wenbin Deng
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077989
• 关键词: Animal Model; Area; Astrocytes; Autologous; Biology; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cell Death; Cell Lineage; Cell Therapy; Cell Transplantation; Cells; Cerebral Ischemia; Cerebral Palsy; Cerebrum; Cicatrix; Clinical; Cognitive; Communication; Data; Demyelinations; Development; Diffuse; Disease; Exhibits; Fibroblasts; Future; Generations; Goals; Human; Hypoxia; Immune; In Vitro; Injury; Investigation; Knowledge; Lead; Lesion; Life; Medical Research; Methods; Modeling; Molecular; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nature; Neonatal; Neonatal Brain Injury; Neuraxis; Neurobiology; Neuroglia; Neurologic; Neurons; Oligodendroglia; Pathogenesis; Pathology; Perinatal; Perinatal Hypoxia; Periventricular Leukomalacia; Periventricular white matter injury; Premature Birth; Premature Infant; Preterm brain injury; Process; Protocols documentation; Rattus; Regulation; Reporting; Research; Social Impacts; Source; Spinal cord injury; Stem Cell Development; Stem cell transplant; Stem cells; System; Testing; Therapeutic; Transplantation; Work; base; cell preparation; clinically relevant; economic impact; effective therapy; human disease; human embryonic stem cell; human embryonic stem cell transplantation; human tissue; in vivo; induced pluripotent stem cell; insight; lung development; mouse model; myelination; neonatal hypoxic-ischemic brain injury; nerve stem cell; nervous system disorder; neuropathology; novel; oligodendrocyte myelination; premature; progenitor; programs; public health relevance; remyelination; repaired; stem; stem cell therapy; white matter; white matter damage

 DESCRIPTION (provided by applicant): Regenerating CNS white matter using induced pluripotent stem cells - Periventricular leukomalacia (PVL) is the leading cause of neurologic morbidity in premature infants leading to cerebral palsy and cognitive problems. The major neuropathologic hallmark of PVL is focal and diffuse periventricular white matter injury, featured by depletion of premyelinating oligodendrocytes (OLs) and myelination disturbances. No effective treatment for PVL is available. Recently, developing cell therapies for neonatal brain injury has gained increasing support. Our lab has identified PVL research as a strategic area of focus for our research program. Our long-term goal is to determine potential stem cell based therapeutic strategies for PVL. Accumulative studies indicate the therapeutic potential for neonatal hypoxic-ischemic injury with transplantation of different stem/progenitor cell preparations. It is prerequisite to derive cells in high purity and homogeneity for developing cell therapies. However, there is currently a common difficulty in obtaining homogenous stem/progenitor cells for transplantation studies and future clinical use. Moreover, the optimal types of cells for transplantation remain unclear. Studies in human tissues and in animal models of PVL showed that there is no lack of oligodendroglia progenitor cells (OPCs), because their proliferation is increased after PVL injury, but their maturation is largely delayed. Cell death is mainly seen in pre- myelinating OLs, but not in neurons. Hence, neuronal progenitors and OPCs may not be the optimal candidates in the PVL injury. Based on our preliminary data, here we propose to develop an astroglia-based cell therapy for neonatal brain injury. Our recent work has led to successful generation of immature astroglia from human embryonic stem cells (hESCs) in high homogeneity and purity (> 95%). We further demonstrated that transplantation of the hESC-derived astrocytes exhibited strong neuroprotective effects both in vitro and in vivo. Astrocytes are increasingly recognized as a crucial player in the myelination process during development and remyelination process after injury. We have been working on generation of human induced pluripotent stem cells (hiPSCs) from fibroblasts and their differentiation into OPCs for myelin regeneration and repair. A main advantage of hiPSCs with respect to hESCs is that they are an unlimited source of isogenic cells that might not be subjected to immune-rejection after transplantation. We have applied our efficient astroglial differentiation protocol o hiPSCs and generated hiPSC-derived immature astroglia. Our preliminary observation indicated that hiPSC-derived immature astrocytes promoted the maturation of OPCs into myelinating oligodendrocytes in vitro. Building upon these previous and preliminary results, we propose to examine whether transplantation of hiPSC-derived astrocytes promotes remyelination after neonatal brain injury in our established mouse PVL model, and the underlying mechanisms will also be explored. This novel study may lead to a new hiPSC-derived astroglia-based cell therapy for PVL, and will also provide new insight into the interaction between OLs and astrocytes, a previously understudied area of investigation. The scientific knowledge to be acquired through this project is of likely benefit to the development of stem cell based therapeutic strategies for treating human neurological disorders such as PVL.

 描述（由申请人提供）：使用诱导多能干细胞再生中枢神经系统白质 - 脑室周围白质软化症 (PVL) 是早产儿神经系统发病的主要原因，导致脑瘫和认知问题。 PVL 的主要神经病理学特征是局灶性和弥漫性。脑室周围白质损伤，其特征是髓鞘形成前少突胶质细胞（OL）耗竭和髓鞘形成障碍。最近，针对PVL的开发细胞疗法获得了越来越多的支持，我们的实验室已将PVL研究确定为我们研究计划的战略重点领域，我们的长期目标是确定潜在的治疗方法。基于干细胞的 PVL 治疗策略表明，移植不同的干细胞/祖细胞制剂具有治疗新生儿缺氧缺血性损伤的潜力，这是获得高纯度和同质性细胞用于发育细胞的先决条件。 然而，目前在获得用于移植研究和未来临床使用的同质干细胞/祖细胞方面存在普遍困难，而且，用于移植的最佳细胞类型仍不清楚。不乏少突神经胶质祖细胞（OPC），因为PVL损伤后它们的增殖增加，但它们的成熟很大程度上被延迟了。 主要见于髓鞘形成前的 OL，但不见于神经元，因此，神经元祖细胞和 OPC 可能不是 PVL 损伤的最佳候选者，在此我们建议开发一种基于星形胶质细胞的新生儿脑细胞疗法。我们最近的工作已经成功地从人类胚胎干细胞（hESC）中产生了高同质性和纯度（> 95％）的未成熟星形胶质细胞。 hESC 衍生的星形胶质细胞在体外和体内均表现出强大的神经保护作用，人们越来越认识到星形胶质细胞在损伤后的髓鞘形成和髓鞘再生过程中发挥着重要作用。 ）从成纤维细胞分化为 OPC 进行髓磷脂再生和修复 hiPSC 相对于 hESC 的一个主要优势是它们是同基因细胞的无限来源。我们将我们的星形胶质细胞分化方案应用于 hiPSC，并生成了 hiPSC 衍生的未成熟星形胶质细胞。我们的初步观察表明，hiPSC 衍生的未成熟星形胶质细胞在体外促进 OPC 有效成熟为髓鞘少突胶质细胞。基于这些先前和初步的结果，我们建议在我们的新生儿脑损伤后检查 hiPSC 衍生的星形胶质细胞的移植是否促进髓鞘再生。建立了小鼠 PVL 模型，并且还将探索其潜在机制，这项新研究可能会导致一种新的基于 hiPSC 的星形胶质细胞治疗 PVL，并且还将为 OL 和星形胶质细胞之间的相互作用提供新的见解，这是之前尚未研究的。通过该项目获得的科学知识可能有利于开发基于干细胞的治疗策略，用于治疗人类神经系统疾病（如PVL）。