Endothelial cell transplantation for multi-organ repair to counter radiation injury

内皮细胞移植用于多器官修复以对抗辐射损伤

• 批准号: 10381505
• 负责人: HANS-PETER KIEM
• 金额: $ 58.64万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-18 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381505
• 关键词: Abnormal Endothelial Cell; Acute; Address; Agonist; Allogenic; Animal Model; Animals; Blood Coagulation Disorders; Blood Vessels; Blood capillaries; Bone Marrow Transplantation; Cell Therapy; Cell Transplantation; Cell physiology; Chronic; Cicatrix; Cirrhosis; Clinic; Clinical; Clinical Engineering; Cryopreservation; Defect; Destinations; Drug Kinetics; Edema; Endothelial Cells; Ensure; Exposure to; Family suidae; Fibrosis; Freezing; Functional disorder; Future; Genetic; Goals; Growth Factor; Guidelines; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hemorrhage; Home; Human; Immune; Impairment; Infection; Inflammation; Injury; Instruction; Intestines; Intravenous; Ionizing radiation; Kinetics; Lead; Life; Liver; Lung; Lymphatic; Lymphatic Endothelial Cells; Macaca nemestrina; Marrow; Measures; Medical; Methods; Modeling; Molecular; Monkeys; Multiple Organ Failure; Mus; Natural regeneration; Neutropenia; Organ; Outcome; Participant; Pathogenesis; Persons; Pharmacodynamics; Preclinical Testing; Procedures; Quality of life; Radiation; Radiation Injuries; Radiation Syndromes; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiation induced damage; Recovery; Rodent; Safety; Schedule; Sclerosis; Secondary to; Signal Transduction; Syndrome; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxic effect; Translating; Transplantation; Tumorigenicity; Umbilical vein; Vascular Graft; Work; angiogenesis; cell bank; cell injury; experimental study; gastrointestinal; healing; hematopoietic engraftment; hematopoietic transplantation; improved; injury and repair; irradiation; liver function; nonhuman primate; operation; organ injury; organ repair; paracrine; preconditioning; premature; prevent; radiation countermeasure; regeneration function; regenerative; repaired; reproductive; restoration; safety testing; secondary infection; senescence; success; therapy development; tumorigenesis; vascular bed

Abstract Exposure to ionizing radiation is often fatal due to acute radiation syndromes (ARS) manifested as Gastrointestinal-ARS (GI-ARS) and Hematopoietic-ARS (H-ARS). Delayed effects of acute radiation exposure (DEARE) lead to multi-organ dysfunction syndrome (MODS). A common denominator of radiation induced multi-organ failure is due to damage to endothelial cells (ECs) and lymphatic ECs, resulting in leakiness, coagulopathy and inflammation, setting up stage for infection, sclerosis and tumorigenesis. The molecular basis of radiation-induced EC dysfunction is not well understood. Our goal is to capitalize on the regenerative function of ECs by intravenously transplanting readily-available, off-the- shelf, allogeneic human ECs to mitigate ARS, DEARE and MODS. Our central hypothesis is that radiation damaged blood vessel and lymphatic ECs become dysfunctional and fail to perform their vascular functions or supply the instructive signals required to promote tissue healing thereby leading to ARS and DEARE. We propose that transplantation of normal pro-regenerative ECs a day or days after radiation can rescue the multi-organ defects of radiation-injured ECs and promote scar-free healing. We have shown that tissue-specific ECs by producing angiocrine growth factors orchestrate the repair of injured organs without fibrosis. Intravenous transplantation of human ECs restores hematopoietic recovery in sublethally irradiated rodents and lethally irradiated pigtail macaque non-human primates (NHP) without fibrosis or tumorigenesis. The Rationale for the proposed experiments is that if we know how to efficiently generate abundant off-the-shelf GMP-grade human umbilical vein ECs (HUVECs) as a “generic allogeneic vascular graft”, we will use NHP large animal model radiation models to determine the pharmacokinetics of HUVEC transplantation to use them as a definitive or intermediary radiation countermeasure to support organ repair post-radiation. We will test this hypothesis by addressing these Aims: 1) Manufacture of abundant functional clinical-grade master cell banks of monkey ECs (MUVECs) and human (HUVECs) for intravenous transplantation. 2) Identify the critical parameters for allogeneic/xenogeneic MUVEC and HUVEC transplantation into recipient mice to mitigate post-irradiation H-ARS and GI-ARS injury without provoking fibrosis..3) Employ pigtail macaque NHP radiation models to determine the scheduling, safety and efficacy of transplanting MUVECs and HUVECs to rejuvenate vascular niche for multi-organ repair without scarring. Completion of the proposed studies will enable therapeutic use of allogeneic off-the-shelf “human ECs” that transiently home to the disrupted vascular beds of irradiated organs restoring angiogenesis and vascular niche functions promoting organ repair, scarring. The success of these studies will provide for a readily available medical counter measure (MCM) for the treatment of acute and chronic radiation syndromes preventing life threatening complications. 1

摘要 暴露于电离辐射通常是致命的，因为急性辐射综合征（ARS）表现为 胃肠道ARS（GI-ARS）和造血ARS（H-ARS）。急性辐射的延迟效应 暴露（DEARE）导致多器官功能障碍综合征（MODS）。的共同点 辐射诱导的多器官衰竭是由于内皮细胞（EC）和淋巴EC的损伤， 导致渗漏、凝血障碍和炎症，为感染、硬化和 肿瘤发生辐射诱导EC功能障碍的分子基础还不清楚。我们的目标 是利用内皮细胞的再生功能， 货架，同种异体人EC，以减轻ARS，DEARE和MODS。我们的核心假设是辐射 受损的血管和淋巴管内皮细胞功能失调， 功能或提供促进组织愈合所需的指导信号，从而导致ARS， 亲爱的。我们认为，辐射后一天或几天移植正常的促再生内皮细胞， 挽救辐射损伤的EC的多器官缺陷并促进无瘢痕愈合。我们已经表明 组织特异性内皮细胞通过产生血管分泌生长因子协调受损器官的修复 没有纤维化。静脉内移植人内皮细胞恢复亚致死性小鼠的造血功能 经辐照的啮齿动物和经致死性辐照的猪尾猕猴非人灵长类动物（NHP），无纤维化或 肿瘤发生所提出的实验的基本原理是，如果我们知道如何有效地生成 大量现成的GMP级人脐静脉内皮细胞（HUVEC）作为“通用同种异体血管内皮细胞”， 移植物”，我们将使用NHP大型动物模型辐射模型来确定HUVEC的药代动力学 移植使用它们作为最终或中间辐射对策，以支持器官 辐射后修复我们将通过解决这些目标来测试这一假设：1）制造大量的 猴EC（MUVEC）和人（HUVEC）的功能性临床级主细胞库，用于 静脉移植2)确定同种异体/异种MUVEC的关键参数， HUVEC移植到受体小鼠中以减轻辐射后H-ARS和GI-ARS损伤， 引起纤维化。3)采用猪尾猕猴NHP辐射模型，确定调度、安全 以及移植MUVECs和HUVECs以再生血管生态位用于多器官修复的功效 没有疤痕完成拟议的研究将使同种异体现成的治疗用途成为可能。 “人类EC”，短暂地回到受辐射器官的受损血管床， 血管生成和血管生态位功能促进器官修复、瘢痕形成。这些研究的成功 将提供一个现成的医疗对策（MCM），用于治疗急性和慢性 放射综合症，防止危及生命的并发症。 1

项目成果

Bioengineering the Bone Marrow Vascular Niche.

• DOI: 10.3389/fcell.2021.645496
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Bessy T;Itkin T;Passaro D
• 通讯作者: Passaro D

Morphological characterization of Etv2 vascular explants using fractal analysis and atomic force microscopy.

使用分形分析和原子力显微镜对 Etv2 血管外植体进行形态学表征。

• DOI: 10.1016/j.mvr.2021.104205
• 发表时间: 2021-11
• 期刊: Microvascular research
• 影响因子: 3.1
• 作者: Adelson RP;Palikuqi B;Weiss Z;Checco A;Schreiner R;Rafii S;Rabbany SY
• 通讯作者: Rabbany SY

Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice.

• DOI: 10.1038/s42003-021-01846-3
• 发表时间: 2021-03-25
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Barcia Durán JG;Lu T;Houghton S;Geng F;Schreiner R;Xiang J;Rafii S;Redmond D;Lis R
• 通讯作者: Lis R

Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction.

• DOI: 10.1016/j.stem.2022.03.002
• 发表时间: 2022-04-07
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Gomez-Salinero, Jesus Maria;Izzo, Franco;Lin, Yang;Houghton, Sean;Itkin, Tomer;Geng, Fuqiang;Bram, Yaron;Adelson, Robert P.;Lu, Tyler M.;Inghirami, Giorgio;Xiang, Jenny Zhaoying;Lis, Raphael;Redmond, David;Schreiner, Ryan;Rabbany, Sina Y.;Landau, Dan A.;Schwartz, Robert E.;Rafii, Shahin
• 通讯作者: Rafii, Shahin

Publisher Correction: Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.

出版商更正：组蛋白变体 H3.3 通过增强染色质适应性来维持成体造血干细胞稳态。

• DOI: 10.1038/s41556-022-00851-w
• 发表时间: 2022
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Guo,Peipei;Liu,Ying;Geng,Fuqiang;Daman,AndrewW;Liu,Xiaoyu;Zhong,Liangwen;Ravishankar,Arjun;Lis,Raphael;BarciaDurán,JoséGabriel;Itkin,Tomer;Tang,Fanying;Zhang,Tuo;Xiang,Jenny;Shido,Koji;Ding,Bi-Sen;Wen,Duancheng;Josefowic
• 通讯作者: Josefowic