Cell Therapy for Neuroprotection in Congenital Heart Disease

先天性心脏病神经保护的细胞疗法

• 批准号: 10744910
• 负责人: Nobuyuki Ishibashi
• 金额: $ 83.72万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744910
• 关键词: Award; Behavioral; Bioinformatics; Bone Marrow; Brain; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Nucleus; Cell Therapy; Cell surface; Cells; Cerebral cortex; Child; Childhood; Chromatin; Classification; Clinical Trials; Data Set; Development; Disease; Enrollment; First Independent Research Support and Transition Awards; Funding; Genetic Transcription; Goals; Growth; Immune; Immune response; Impairment; Infant; Infusion procedures; Knowledge; Mediating; Messenger RNA; MicroRNAs; Mining; Molecular; Molecular Profiling; Neuroglia; Neurologic; Neurological outcome; Nuclear; Oligodendroglia; Outcome; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Play; Population; Postoperative Period; Process; Publishing; Recovery; Regulatory T-Lymphocyte; Repair Complex; Resolution; Role; Signal Pathway; Structure; System; Testing; Therapeutic; Time; Tissues; Transcript; Treatment Efficacy; bench-to-bedside translation; congenital heart disorder; differential expression; executive function; exosome; extracellular vesicles; frontal lobe; glial activation; immunoregulation; improved; mesenchymal stromal cell; nerve stem cell; neural; neuron apoptosis; neuron regeneration; neuroprotection; novel; novel strategies; novel therapeutics; optimal treatments; porcine model; postnatal; prevent; progenitor; regenerative; repaired; response; single-cell RNA sequencing; stem; stem cells; subventricular zone; tissue injury; tissue regeneration; tissue repair; transcriptome; transcriptome sequencing; transcriptomics; unpublished works; white matter

PROJECT SUMMARY Significant neurological delay is emerging as one the most important current challenges for children with congenital heart disease (CHD), yet few treatment options are currently available. In our first period of funding, we proposed the use of cardiopulmonary bypass (CPB) as a cell delivery system in infants with CHD as a novel approach for improving the neurological impairments in CHD. Our published and unpublished work has demonstrated the efficacy and utility of this approach, determining the systemic effects of delivery bone marrow- derived mesenchymal stromal cell (BM-MSC) via CPB and the effect on white matter (WM) and sub-ventricular zone (SVZ) development. Most notably, the first award successfully led to development of a phase 1 clinical trial termed “MeDCaP” at Children’s National. Using our translational piglet model, we have demonstrated cellular, structural, and behavioral improvements after BM-MSC delivery through CPB and generated critical information for bench-to-bedside translation. However, the mechanisms underlying the therapeutic action of BM-MSCs still remain largely unknown. This R01 renewal will address the key knowledge gaps with the goal of further enhancing our cell-based treatment for neuroprotection in the CHD population. Exosome is a class of extracellular vesicles loaded with bioactive molecules such as microRNA (miRNA). Exosomes derived from BM- MSCs (BM-MSCexo) can play a major role in the effects on surrounding cells and tissues and elicit favorable responses in various diseases. We have established a pipeline for post-cell delivery integrated transcriptomic analysis of exosomal miRNAs from BM-MSCs and host tissue mRNA. Our preliminary studies have identified the BM-MSCexo-derived miRNAs as putative key drivers of reduced neuronal apoptosis and microglial activation observed after BM-MSC treatment in the cerebral cortex. The overarching goal of this renewal proposal is to establish detailed molecular signatures from critical cell populations for tissue repair and regeneration at single cell resolution after BM-MSC delivery; we will then use those molecular signatures as roadmaps to identify novel molecular entities within the BM-MSCexo that account for the disease-modifying bioactivity in tissue injury after pediatric cardiac surgery. The renewal studies will test our central hypothesis that specific exosomal cargo constituents from BM-MSCs promote repair and regenerative processes both through neural progenitors and regulatory T cells, thereby improving neurological outcomes and post-operative course. To retroactively identify key exosomal bioactive molecules, we will determine the transcriptional and chromatin landscape of three specific cell populations: 1) SVZ neural stem and progenitor cells; 2) WM oligodendrocytes; and 3) regulatory T cells. Together with our ongoing clinical trial established based on the previous award, identifying molecular signatures of BM-MSC treatment and mining specific BM-MSCexo for unique CPB pathology will significantly improve our understanding of this cell-based treatment and will provide a new therapeutic paradigm for potential cell-free MSC-based therapies for neuroprotection in children with CHD.

项目摘要 显着的神经延迟正在成为当前最重要的挑战 先天性心脏病（CHD），但目前几乎没有治疗选择。在我们的第一阶段， 我们提出了将心肺旁路（CPB）用作冠心病婴儿的细胞输送系统的使用 改善CHD中神经系统障碍的方法。我们发表的未发表的工作 证明了这种方法的有效性和效用，确定了递送骨髓的系统效应 通过CPB衍生的间充质基质细胞（BM-MSC）以及对白质（WM）和室内的影响 区域（SVZ）开发。最值得注意的是，第一个奖项成功地导致了第一阶段临床试验的发展 在儿童国民上被称为“ Medcap”。使用我们翻译的仔猪模型，我们证明了细胞， BM-MSC通过CPB交付后的结构和行为改进并产生了关键信息 用于卧铺翻译。但是，BM-MSC的治疗作用的基础机制仍然 在很大程度上未知。此R01更新将解决关键知识差距，以进一步的目标 增强了我们基于细胞的冠心病群体中基于细胞的神经保护治疗。外泌体是一类 带有生物活性分子（例如microRNA（miRNA））的细胞外蔬菜。源自BM-的外泌体 MSC（BM-MSCEXO）可以在对周围细胞和组织的影响中起主要作用，并引起有利的 各种疾病的反应。我们已经建立了一条用于细胞后输送集成转录组的管道 BM-MSC和宿主组织mRNA的外泌体miRNA分析。我们的初步研究已经确定 BM-MSCEXO衍生的miRNA是降低神经元凋亡和小胶质细胞激活的推定关键驱动因素 在大脑皮层中BM-MSC处理后观察到。该更新建议的总体目标是 从关键细胞种群中建立的详细分子特征，用于组织修复和再生。 BM-MSC输送后的细胞分辨率；然后，我们将使用这些分子特征作为路线图来识别新颖 BM-MSCEXO内的分子实体，该实体解释了在组织损伤中改善疾病的生物活性 小儿心脏手术。更新研究将检验我们的中心假设，即特定的外泌体货物 由BM-MSC构成的促进通过神经祖细胞和再生过程的修复和再生过程 调节性T细胞，从而改善神经系统结局和术后课程。追溯识别 关键的外泌体生物活性分子，我们将确定三个转录和染色质景观 特定细胞群：1）SVZ神经茎和祖细胞； 2）wm少突胶质细胞； 3）监管t 细胞。以及我们正在进行的临床试验基于先前的奖项，确定分子 BM-MSC治疗和针对独特CPB病理学的挖掘特异性BM-MSCEXO的签名将显着 提高我们对这种基于细胞的治疗的理解，并将为潜在的新治疗范式提供新的治疗范式 CHD儿童的神经保护性神经保护疗法的无细胞MSC疗法。

项目成果

Defining the optimal historical control group for a phase 1 trial of mesenchymal stromal cell delivery through cardiopulmonary bypass in neonates and infants.

为新生儿和婴儿通过心肺旁路输送间充质基质细胞的一期试验定义最佳历史对照组。

• DOI: 10.1017/s1047951122002633
• 发表时间: 2023
• 期刊: Cardiology in the young
• 影响因子: 1
• 作者: Kobayashi,Kei;Higgins,Tessa;Liu,Christopher;Ayodeji,Mobolanle;Wernovsky,Gil;Jonas,RichardA;Ishibashi,Nobuyuki
• 通讯作者: Ishibashi,Nobuyuki

Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity.

• DOI: 10.1016/j.tins.2022.03.007
• 发表时间: 2022-06
• 期刊: TRENDS IN NEUROSCIENCES
• 影响因子: 15.9
• 作者: Sari, Nemanja;Hashimoto-Torii, Kazue;Jevtovic-Todorovic, Vesna;Ishibashi, Nobuyuki
• 通讯作者: Ishibashi, Nobuyuki

Application of a neuroscience research model to study neuroprotection in children with congenital heart disease.

应用神经科学研究模型研究先天性心脏病儿童的神经保护。

• DOI: 10.1016/j.jtcvs.2018.06.067
• 发表时间: 2018
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: Ishibashi,Nobuyuki;Jonas,RichardA
• 通讯作者: Jonas,RichardA

Mesenchymal Stromal Cell Delivery Via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Model.

• DOI: 10.1016/j.jacbts.2023.07.002
• 发表时间: 2023-12
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Sarkislali, Kamil;Kobayashi, Kei;Saric, Nemanja;Maeda, Takuya;Henmi, Soichiro;Somaa, Fahad A.;Bansal, Ankush;Tu, Shao Ching;Leonetti, Camille;Hsu, Chao-Hsiung;Li, Jingang;Vyas, Pranav;Kawasawa, Yuka Imamura;Tu, Tsang-Wei;Wang, Paul C.;Hanley, Patrick J.;Hashimoto-Torii, Kazue;Frank, Joseph A.;Jonas, Richard A.;Ishibashi, Nobuyuki
• 通讯作者: Ishibashi, Nobuyuki

[Formula: see text] Trajectories of neurodevelopment and opportunities for intervention across the lifespan in congenital heart disease.

[公式：见文字]先天性心脏病的神经发育轨迹和整个生命周期的干预机会。

• DOI: 10.1080/09297049.2023.2173162
• 发表时间: 2023
• 期刊: Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence
• 作者: Sanz,JacquelineH;Cox,Stephany;Donofrio,MaryT;Ishibashi,Nobuyuki;McQuillen,Patrick;Peyvandi,Shabnam;Schlatterer,Sarah
• 通讯作者: Schlatterer,Sarah