Embryonic Stem Cell Derived HSC Transplantation in Rhesus Macaque Model

恒河猴模型中胚胎干细胞衍生的 HSC 移植

基本信息

批准号：
8100196
负责人：
PEIMAN HEMATTI
金额：
$ 13.64万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-14 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8100196
关键词：
Adult Animal Model Bone Marrow CD34 gene Cell Line Cell Therapy Cells Chimerism Clinical Coculture Techniques Developmental Biology Disease ES Cell Line Embryo Engraftment Gene Proteins Gene Transfer Gene-Modified Generations Genes Goals Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Immunodeficient Mouse In Vitro Macaca mulatta Malignant - descriptor Mesenchymal Methodology Modeling Mus NOD/SCID mouse Non-Malignant Patients Play Population Pre-Clinical Model Primates Principal Investigator Process Proteins Recombinants Research Research Personnel Role Safety Siblings Source Stromal Cells Testing Therapeutic Tissues Transplantation Umbilical Cord Blood Undifferentiated abstracting clinical application design efficacy evaluation embryonic stem cell human embryonic stem cell improved in vitro Assay in vivo mouse model nonhuman primate novel peripheral blood pre-clinical programs reconstitution research study stem cell differentiation transcription factor

项目摘要

DESCRIPTION (provided by applicant): Although adult hematopoietic stem cells (HSCs) are being used routinely in clinical transplantation, the lack of a suitable source of donor cells remains a major limiting factor depriving many patients of this potentially curative treatment. The ultimate goal of the Principal Investigator is to generate HSCs from embryonic stem cells (ESCs) as a novel source of cells suitable for clinical transplantation. We are proposing an intensive research program to study the developmental biology of hematopoiesis from rhesus ESCs, and to establish the rhesus macaque model as a relevant pre-clinical large animal model for the evaluation of the efficacy and safety of ESCderived HSCs. Using methodologies such as co-culturing with mesenchymal stromal cells (MSC) of murine bone marrow origin, non-human primate and human ESCs have been differentiated into primitive hematopoietic cells as defined by surrogate in vitro assays. However, those derived cells have been shown to possess only limited in vivo engraftment potential upon transplantation into NOD/SCID immunodeficient mice. Our underlying hypothesis is that by providing the appropriate extrinsic and intrinsic inductive mechanisms that play critical roles in embryonic hematopoiesis, we can effectively recapitulate those processes in vitro and thus promote the efficient differentiation of rhesus ESCs into HSCs that will be capable of engraftment and long-term hematopoietic reconstitution in vivo. In aim-1 we will generate MSC cells from rhesus ESCs and will test their potential as a hematopoietic supportive microenvironment in coculture experiments for the generation of HSCs from rhesus ESCs. In aim-2 we will test our hypothesis that the over-expression of HOXB4, a transcription factor which plays a key role in embryonic hematopoiesis, in rhesus ESCs via gene transfer, or the exogenous delivery of the HOXB4 protein, can improve the efficiency of their differentiation into HSCs. In aim-3 we will assess the in vivo engraftment potential of hematopoietic cells derived from rhesus ESCs alone or when co-transplanted with rhesus ESC-derived MSCs into NOD/SCID mice as we hypothesize that the co-transplantation of rhesus ESC-derived MSCs would potentially provide an appropriate niche and thus enhance the in vivo engraftment potential of rhesus ESCderived HSCs. The results of these proposed studies would help us to design a rational approach toward moving such cells into actual rhesus transplantation experiments. Embryonic stem cells have the potential to generate an unlimited number of diverse differentiated cells for human therapeutic applications including hematopoietic stem cells. We are proposing to develop a rhesus monkey transplantation model to study the efficacy and safety of such cells as they should be carefully tested in appropriate pre-clinical animal models before being moved into human clinical applications. (End of Abstract)

描述（由申请人提供）：尽管成体造血干细胞（HSC）在临床移植中常规使用，但缺乏合适的供体细胞来源仍然是许多患者无法获得这种潜在治愈性治疗的主要限制因素。首席研究员的最终目标是从胚胎干细胞 (ESC) 中产生 HSC，作为适合临床移植的新型细胞来源。我们正在提出一项深入研究计划，研究恒河猴ESC造血的发育生物学，并建立恒河猴模型作为相关的临床前大型动物模型，用于评估ESC衍生的HSC的有效性和安全性。使用与小鼠骨髓来源的间充质基质细胞 (MSC) 共培养等方法，非人灵长类动物和人类 ESC 已分化为替代体外测定所定义的原始造血细胞。然而，这些衍生细胞在移植到 NOD/SCID 免疫缺陷小鼠体内后仅具有有限的体内植入潜力。我们的基本假设是，通过提供在胚胎造血中发挥关键作用的适当的外在和内在诱导机制，我们可以有效地在体外重现这些过程，从而促进恒河猴 ESC 有效分化为能够植入并长期存活的 HSC。术语体内造血重建。在 Target-1 中，我们将从恒河猴 ESC 中生成 MSC 细胞，并在共培养实验中测试它们作为造血支持微环境的潜力，以从恒河猴 ESC 中生成 HSC。在 Target-2 中，我们将检验我们的假设，即通过基因转移或外源递送 HOXB4 蛋白在恒河猴 ESC 中过表达 HOXB4（一种在胚胎造血中起关键作用的转录因子）可以提高造血效率。它们分化为 HSC。在目标 3 中，我们将评估单独源自恒河猴 ESC 的造血细胞或与恒河猴 ESC 衍生的 MSC 共同移植到 NOD/SCID 小鼠中时的体内植入潜力，因为我们假设恒河猴 ESC 衍生的 MSC 的共移植可能会提供适当的生态位，从而增强恒河猴 ESC 衍生的 HSC 的体内植入潜力。这些拟议研究的结果将帮助我们设计一种合理的方法，将这些细胞转移到实际的恒河猴移植实验中。胚胎干细胞有潜力产生无限数量的多样化分化细胞，用于人类治疗应用，包括造血干细胞。我们建议开发恒河猴移植模型来研究此类细胞的功效和安全性，因为在进入人类临床应用之前，应在适当的临床前动物模型中仔细测试它们。（摘要完）

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）

Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.

DOI：
10.1016/j.exphem.2009.09.004
发表时间：
2009-12
期刊：
EXPERIMENTAL HEMATOLOGY
影响因子：
2.6
作者：
Kim, Jaehyup;Hematti, Peiman
通讯作者：
Hematti, Peiman

Generation of mesenchymal stromal cells from HOXB4-expressing human embryonic stem cells.

从表达 HOXB4 的人胚胎干细胞产生间充质基质细胞。

DOI：
10.3109/14653240903051566
发表时间：
2009
期刊：
Cytotherapy
影响因子：
4.5
作者：
Liu,Yi-Ping;Hematti,Peiman
通讯作者：
Hematti,Peiman

Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model.

DOI：
10.3109/14653240903067299
发表时间：
2009
期刊：
Cytotherapy
影响因子：
4.5
作者：
Laurila JP;Laatikainen L;Castellone MD;Trivedi P;Heikkila J;Hinkkanen A;Hematti P;Laukkanen MO
通讯作者：
Laukkanen MO

Human embryonic stem cell-derived mesenchymal stromal cells.

DOI：
10.1111/j.1537-2995.2011.03376.x
发表时间：
2011-11
期刊：
Transfusion
影响因子：
2.9
作者：
Hematti P
通讯作者：
Hematti P

Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells.

DOI：
10.1111/j.1365-2141.2012.09154.x
发表时间：
2012-08
期刊：
British journal of haematology
影响因子：
6.5
作者：
Kim J;Denu RA;Dollar BA;Escalante LE;Kuether JP;Callander NS;Asimakopoulos F;Hematti P
通讯作者：
Hematti P