Functional recovery from acute brain injury via human neural stem cell transplantation

通过人类神经干细胞移植从急性脑损伤中恢复功能

• 批准号: 8813364
• 负责人: JASON P WEICK
• 金额: $ 28.47万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813364
• 关键词: Acute; Acute Brain Injuries; Address; Adult; Adverse effects; Aging; American; Anatomy; Animal Model; Animals; Baby Booms; Behavior; Behavioral; Brain; Cause of Death; Cell Transplants; Cells; Cerebral Ischemia; Chronic; Clinical Trials; Data; Dependence; Disabled Persons; Epidemic; Future; Generations; Goals; Health; Heart Diseases; Human; In Vitro; Incidence; Individual; Inflammation; Injury; Intervention; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Left; Mediating; Modeling; Motor; Neuronal Plasticity; Neurons; New Mexico; Optics; Outcome; Output; Pathway interactions; Patients; Peripheral; Phase I Clinical Trials; Plant Roots; Pluripotent Stem Cells; Prevention; Process; Recovery; Recovery of Function; Replacement Therapy; Reporting; Safety; Sensorimotor functions; Sensory; Societies; Stem cell transplant; Stem cells; Stroke; Survivors; Synapses; Testing; Therapeutic Intervention; Time; Tissues; Transplantation; Treatment Efficacy; United States; Universities; angiogenesis; base; behavioral outcome; brain cell; brain tissue; cell type; cost; disability; effective therapy; human embryonic stem cell; human stem cells; improved; in vivo; insight; ischemic lesion; mouse model; nerve stem cell; nerve supply; neurotransmitter release; optogenetics; paracrine; pre-clinical; preclinical study; progenitor; relating to nervous system; repaired; research study; sensory system; simulation; stroke recovery; vesicular release

SUMMARY Stroke represents a major health issue not only as a cause of death but because most people survive their first stroke, leaving victims permanently disabled. With an aging baby boom generation in the United States, incidence of stroke and costs to society propose to reach epidemic proportions within the next two decades. While prevention efforts have significantly reduced lethality, few effective treatment options exist to provide patients with a means of recovery, and none exist to address the root cause of the problem, loss of brain tissue. Recently however, successful outcomes from cell replacement therapies in pre-clinical studies have led to a number of clinical trials which have demonstrated safety and efficacy for a variety of cell types. Interestingly, many of the mechanisms attributed to transplanted mediated recovery converge on the activity- regulated release of paracrine factors from transplant to host. In the current study, we propose first to validate that transplanted human pluripotent stem cell-derived neurons (hPSNs) improve behavioral recovery in a mouse model of focal ischemia that is amenable to mechanistic and manipulation studies (Specific Aim 1). We will then use this model to test whether optogenetic stimulation of hPSNs can augment behavioral recovery from stroke (Specific Aim 2). Lastly, multiple lines of evidence suggest that functional integration of transplanted cells with host tissue is critical for long-term benefits of cell replacement. In support of this, we have recently demonstrated in uninjured animals that human embryonic stem cell-derived neurons (hPSNs) can functionally integrate with host circuitry after transplantation, and can cause changes to overall excitability in vitro. In the Specific Aim 3 we will test whether and how transplanted hPSNs are functionally integrating with host circuits in vivo to understand how we might augment future intervention strategies. The impact of answering these questions proposes to improve efficacy of cell-based therapeutic interventions.

总结 中风是一个主要的健康问题，不仅是死亡的原因，而且因为大多数人在第一次中风后都能存活下来。 中风，使受害者终身残疾。随着美国婴儿潮一代的老龄化， 中风的发病率和社会成本预计将在未来20年内达到流行病的比例。 虽然预防工作大大降低了致死率，但几乎没有有效的治疗选择， 病人有了康复的手段，而没有一个存在的问题，以解决根本原因，失去大脑 组织.然而，最近，临床前研究中细胞替代疗法的成功结果导致了 许多临床试验已经证明了对各种细胞类型的安全性和有效性。 有趣的是，许多机制归因于移植介导的恢复收敛于活性- 从移植物到宿主的旁分泌因子的调节释放。在目前的研究中，我们建议首先验证 移植的人类多能干细胞衍生神经元（hPSNs）改善了行为恢复， 适于机理和操作研究的局灶性缺血小鼠模型（具体目标1）。我们 然后将使用该模型来测试hPSNs的光遗传学刺激是否可以增强行为恢复 具体目标2（Specific Aim 2）最后，多方面的证据表明， 将细胞与宿主组织一起移植对于细胞替代的长期益处是至关重要的。为了支持这一点，我们 最近在未受伤的动物中证明，人类胚胎干细胞衍生的神经元（hPSNs） 移植后可与宿主电路功能性整合，并可引起整体兴奋性的变化 体外在具体目标3中，我们将测试移植的hPSN是否以及如何在功能上与 宿主体内电路，以了解我们如何增强未来的干预策略。的影响 回答这些问题提出了提高基于细胞的治疗干预的功效。