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Mechanically controlled release of hematopoietic factors from mesenchymal stromal cells for blood regeneration

机械控制间充质基质细胞释放造血因子用于血液再生

基本信息

批准号：
8979703
负责人：
Jae-Won Shin
金额：
$ 8.75万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-01-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8979703
关键词：
Address Affect American Award Biocompatible Materials Biodistribution Biological Biomechanics Biomedical Engineering Blood Blood Circulation Bone Marrow CD34 gene Cell Count Cell Differentiation process Cells Clinical Cues Data Disease Encapsulated Engineering Engraftment Ensure Exhibits Exocytosis Extracellular Matrix Fluorouracil Gel General Hospitals Goals Growth Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homologous Transplantation Human Hydrogels Immunocompromised Host In Vitro Infusion procedures Injectable Integrins Laboratories Ligands Malignant Neoplasms Massachusetts Measures Mechanics Mesenchymal Methods Microfluidics Mus Myosin Phosphatase Pathway Natural regeneration Patients Phase Population Process Property Protein Secretion RNA Interference Research Research Personnel Role Signal Transduction Source Stem cells Stromal Cells System Technology Testing Therapeutic Effect Tissue Engineering Training Transplantation Universities Work Xenograft procedure base controlled release density design experience in vivo in vivo regeneration migration miniaturize novel strategies novel therapeutics paracrine programs public health relevance release factor response small molecule standard care stem cell niche technology development three dimensional cell culture transcription factor

项目摘要

DESCRIPTION (provided by applicant): Project Summary Hematopoietic stem cell (HSC) transplantation has been used as a standard treatment for a number of hematopoietic disorders and malignancies to achieve blood regeneration in many patients. However, procuring a sufficient number of compatible HSC sources for patients who need allogeneic transplantation remains challenging, and thus only a fraction of the patients undergo transplantation. Therefore, new advances are needed to develop strategies to either expand HSCs ex vivo or regenerate HSCs in vivo. Multipotent bone marrow (BM) mesenchymal stromal cells (MSCs) are the major constituents of the HSC niche in the bone marrow, providing key regulatory signals to program hematopoiesis. How MSCs can be harnessed remains an important goal to achieve clinical benefits for blood regeneration. Advances in the field of biomechanics have revealed that a range of matrix stiffness exhibited by the native BM milieu elicits profound contractile force- dependent biological responses in MSCs. The goal of this proposal is thus to evaluate the potential of biomaterials with tunable matrix stiffness for use in controlling MSCs to facilitate blood regeneration. The overall hypothesis is that matrix stiffness controls secretion of proteins from MSCs, and in turn, influences hematopoiesis in a paracrine manner. The specific aims include: (1) Elucidate mechanisms behind matrix stiffness-dependent release of hematopoietic factors from MSCs. (2) Engineer injectable hydrogel microdroplets that can encapsulate single MSCs with tunable matrix stiffness. (3) Assess the therapeutic effect of MSCs in hydrogel microdroplets on human blood regeneration in vivo. During the K99 training period, this award will be used to further the candidate's training in stem cell mechanobiology, and for him to become competent in physical approaches to biomaterial design and advanced microtechnologies. This research will be conducted in a major bioengineering laboratory at Harvard University that focus on biomaterial-based technology development for tissue engineering and studying mechanotransduction, with close clinical connections at Massachusetts General Hospital. This experience will ensure a smooth transition into the R00 phase for the candidate to become an independent translational investigator at the interface between mechanobiology and bioengineering to develop novel therapeutic strategies for hematopoietic disorders.

描述（由申请人提供）：项目概要造血干细胞（HSC）移植已被用作许多造血系统疾病和恶性肿瘤的标准治疗方法，以实现许多患者的血液再生。然而，为需要同种异体移植的患者采购足够数量的兼容HSC来源仍然具有挑战性，因此只有一小部分患者接受了移植。因此，需要新的进展来制定离体扩增 HSC 或体内再生 HSC 的策略。多能骨髓 (BM) 间充质基质细胞 (MSC) 是骨髓中 HSC 生态位的主要成分，为造血程序提供关键的调节信号。如何利用间充质干细胞仍然是实现血液再生临床效益的一个重要目标。生物力学领域的进展表明，天然骨髓环境表现出的一系列基质刚度在 MSC 中引发了深刻的收缩力依赖性生物反应。因此，该提案的目标是评估具有可调节基质刚度的生物材料用于控制 MSC 以促进血液再生的潜力。总体假设是基质硬度控制 MSC 蛋白质的分泌，进而以旁分泌方式影响造血作用。具体目标包括：（1）阐明间充质干细胞基质硬度依赖性造血因子释放背后的机制。 (2) 设计可注射的水凝胶微滴，可以封装具有可调基质硬度的单个 MSC。 (3) 评估水凝胶微滴中的间充质干细胞对人体血液再生的体内治疗效果。在K99培训期间，该奖项将用于进一步加强候选人在干细胞力学生物学方面的培训，并使他能够胜任生物材料设计和先进微技术的物理方法。这项研究将在哈佛大学的一个主要生物工程实验室进行，该实验室专注于基于生物材料的组织工程技术开发和研究机械传导，并与马萨诸塞州总医院有密切的临床联系。这一经验将确保候选人顺利过渡到 R00 阶段，成为机械生物学和生物工程交叉领域的独立转化研究者，以开发造血系统疾病的新型治疗策略。