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

基本信息

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
项目类别：
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

项目摘要

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

抽象的暴露于电离辐射通常是由于急性辐射综合征（AR）表现为胃肠道（GI-ARS）和造血-ARS（H-AR）。急性辐射的延迟作用暴露（亲爱的）导致多器官功能障碍综合征（mod）。一个共同的分母辐射引起的多器官故障是由于对内皮细胞（EC）和淋巴EC的损害造成的，导致渗漏，凝血病和感染，为感染，硬化症和肿瘤发生。辐射诱导的EC功能障碍的分子基础尚不清楚。我们的目标是通过静脉移植易于使用的，无效的，利用EC的再生功能架子，同种异体人类EC，以减轻Ars，Deare和Mods。我们的中心假设是辐射受损的血管和淋巴EC会功能失调，无法进行血管功能或提供促进组织愈合所需的指导性信号，从而导致AR和亲爱的。我们建议每天或几天在辐射后每天或天挽救受辐射造成的EC的多器官缺陷并促进无疤痕愈合。我们已经显示了通过产生血管分泌生长因子来策划受伤器官的修复，该组织特异性EC 没有纤维化。人类ECS的静脉移植可恢复造血恢复没有纤维化或肿瘤发生。提出的实验的理由是，如果我们知道如何有效产生富有现成的GMP级人脐静脉EC（HUVEC）作为“通用同种异体血管移植”，我们将使用NHP大型动物模型辐射模型来确定HUVEC的药代动力学移植以将其用作确定或中间辐射对策以支持器官维修后辐射。我们将通过解决这些目标来检验这一假设：1）绝对制造猴子ECS（MUVECS）和人类（HUVECS）的功能性临床级主细胞库静脉移植。 2）确定同种异体/异种MUVEC的关键参数和 HUVEC移植到接受者小鼠中，以减轻辐射后H-AR和GI-ARS损伤挑衅纤维化..3）采用辫子猕猴NHP辐射模型来确定调度并易于移植MUVEC和HUVECS，使血管生态位恢复活力没有疤痕。拟议研究的完成将实现同种异体现成的治疗使用 “人类EC”瞬时地恢复了辐照器官的血管床血管生成和血管生态位功能促进器官修复，疤痕。这些研究的成功将为急性和慢性治疗提供随时可用的医疗柜台措施（MCM）辐射综合征可防止威胁生命的并发症。 1

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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