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zone; tissue injury; tissue regeneration; tissue repair; transcriptome; transcriptome sequencing; transcriptomics; unpublished works; white matter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 Our published and unpublished work has demonstrated the efficacy and utility of this approach, determining the systemic effects of delivery bone marrow- derived mesenchymal stromal cell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 严重的神经延迟正在成为儿童目前最重要的挑战之一， 先天性心脏病（CHD），但目前几乎没有治疗选择。在我们的第一次融资中， 我们建议使用心肺转流（CPB）作为CHD婴儿的细胞输送系统， 改善CHD神经功能障碍的方法。我们已发表和未发表的作品 证明了这种方法的有效性和实用性，确定了骨髓输送的全身效应， 体外循环诱导骨髓间充质干细胞（BM-MSC）的体外培养及其对白色物质（WM）和室下膜的影响 开发区（SVZ）。最值得注意的是，第一个奖项成功地导致了1期临床试验的发展 在全国儿童协会被称为“MeDCaP”使用我们的翻译小猪模型，我们已经证明了细胞， 通过CPB交付BM-MSC后的结构和行为改进，并生成关键信息 从工作台到床边的翻译然而，BM-MSCs的治疗作用的机制仍然是未知的。 但基本上仍不为人所知。此次R 01更新将解决关键的知识差距，目标是进一步 加强我们的细胞为基础的治疗冠心病人群的神经保护。外泌体是一类 细胞外囊泡装载有生物活性分子如微小RNA（miRNA）。来源于BM的外来体- 骨髓间充质干细胞（BM-MSCexo）可以在对周围细胞和组织的影响中发挥重要作用，并引起有利的细胞分化。 各种疾病的反应。我们已经建立了一个细胞后递送整合转录组学的管道， 来自BM-MSC和宿主组织mRNA的外来体miRNA的分析。我们的初步研究发现 BM-MSCexo衍生的miRNA是减少神经元凋亡和小胶质细胞活化的假定关键驱动因素 BM-MSC处理后在大脑皮层中观察到。这一更新提案的总体目标是 从关键细胞群中建立详细的分子特征，用于组织修复和再生， BM-MSC交付后的细胞分辨率;然后，我们将使用这些分子标记作为路线图，以确定新的 BM-MSCexo中的分子实体，其解释了在治疗后组织损伤中的疾病修饰生物活性， 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 来自BM-MSC的成分通过神经祖细胞和神经胶质细胞促进修复和再生过程， 调节性T细胞，从而改善神经系统的结果和术后过程。追溯识别 关键外泌体生物活性分子，我们将确定转录和染色质景观的三个 特异性细胞群：1）SVZ神经干细胞和祖细胞; 2）WM少突胶质细胞;和3）调节性T细胞 细胞与我们正在进行的临床试验建立在以前的奖项，确定分子 BM-MSC治疗的特征和针对独特CPB病理学的特定BM-MSCexo的挖掘将显著 提高我们对这种基于细胞的治疗的理解，并将提供一种新的治疗模式， 基于无细胞MSC的治疗对CHD儿童的神经保护作用。

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

The Current Status of Neuroprotection in Congenital Heart Disease.

• DOI: 10.3390/children8121116
• 发表时间: 2021-12-02
• 期刊: Children (Basel, Switzerland)
• 作者: Kobayashi K;Liu C;Jonas RA;Ishibashi N
• 通讯作者: Ishibashi N