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

• 批准号: 8805621
• 负责人: Jae-Won Shin
• 金额: $ 8.85万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805621
• 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 Factor; 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; Plastics; 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; transcription factor

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）：项目摘要造血干细胞（HSC）移植已被用作许多造血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。但是，为需要同种异体移植的患者购买足够数量的兼容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，需要新的进步来制定策略以在体内扩展HSC或在体内再生HSC。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，为造血造血提供了关键的调节信号。如何利用MSC仍然是实现血液再生临床益处的重要目标。生物力学领域的进步表明，本地BM环境表现出的一系列基质刚度引起了MSC中深厚的收缩力依赖性生物学反应。因此，该提案的目的是评估具有可调基质刚度的生物材料的潜力，用于控制MSC以促进血液再生。总体假设是基质刚度控制MSC的蛋白质分泌，进而以旁分泌方式影响造血。具体目的包括：（1）阐明基质刚度依赖性释放造血因子的机制。 （2）可以用可调矩阵刚度封装单个MSC的工程师注射水凝胶微芯。 （3）评估MSC在水凝胶微核对体内人体血液再生中的治疗作用。在K99培训期间，该奖项将用于进一步促进候选人在干细胞机械生物学方面的培训，并使他能够在生物材料设计和高级微观技术方面胜任。这项研究将在哈佛大学的一项主要生物工程实验室进行，该实验室的重点是基于生物材料的技术开发，用于组织工程和研究机械转导的技术，并在马萨诸塞州综合医院进行了紧密的临床联系。这种经验将确保候选人成为R00阶段的平稳过渡，以成为机械生物学和生物工程之间的界面的独立翻译研究者，以开发用于造血疾病的新型治疗策略。