Identifying hMSC interaction pathways in soluble interferon-gamma and stratified collagen/heparin coatings for the manufacturing of therapeutic cells

鉴定用于制造治疗细胞的可溶性干扰素-γ和分层胶原/肝素涂层中的 hMSC 相互作用途径

• 批准号: 2051582
• 负责人: Jorge Almodovar
• 金额: $ 48.64万
• 依托单位: University of Arkansas
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2051582&HistoricalAwards=false
• 关键词: Identifying; hMSC; interaction; pathways; soluble

Human mesenchymal stromal cells (hMSC) show promise for treating deadly incurable diseases. One of the main limitations of hMSC production is the growth of fully functional cells in bioreactors. Treatment with interferon gamma (IFN) enhances the therapeutic potency of hMSCs but also inhibits growth. Coating hMSCs with layers of collagen (COL) and heparin (HEP) reduces the inhibition while maintaining the therapeutic enhancement, but it is unknown how the layers cause this to occur. This project will identify the specific pathways by which COL/HEP coatings enhance hMSC response to IFN. This knowledge will support the design of optimal bioreactor platforms for the manufacturing of highly therapeutic cells. Students from underrepresented populations will engage in research at the interface between engineering and biology. This will help develop a strong and diverse biomanufacturing workforce.The central hypothesis of this project is that COL/HEP coatings work synergistically with soluble IFN to modulate signaling pathways regulating proliferation and immunosuppressive properties. This hypothesis was formulated, in large part, based on preliminary data indicating that COL/HEP coatings: induce expression of basic fibroblast growth factor (FGF2) and reduce the anti-proliferative effect of IFN while enhancing immunomodulatory cytokine secretion. The specific objectives are: (1) To establish the relationship between the coatings and the activation of the FGF2 pathway in hMSCs, and its relation to proliferation; (2) To establish the mechanism by which IFN activates hMSCs cultured on COL/HEP coatings; and (3) To determine the extent to which COL/HEP coatings remain consistent when translated to microcarriers for suspension-based bioreactors. This project will directly impact the cell manufacturing field by merging polymeric materials with biochemical signals to produce a technology that enhances hMSCs activation and therapeutic potency.This project is jointly funded by the Cellular and Biochemical Engineering Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

人骨髓间充质干细胞(HMSC)在治疗致命的不治之症方面显示出良好的前景。HMSC生产的主要限制之一是在生物反应器中生长全功能细胞。干扰素治疗可增强hMSCs的治疗效力，但也会抑制生长。用胶原层(Col)和肝素(Hep)包被hMSCs可以在保持治疗增强的同时减少抑制，但目前尚不清楚这些层是如何导致这种情况发生的。本项目将确定COL/HEP涂层增强hMSC对干扰素应答的具体途径。这些知识将支持设计最佳的生物反应器平台，以制造高度治疗性的细胞。来自代表性不足人群的学生将从事工程学和生物学之间的研究。这将有助于发展一支强大和多样化的生物制造队伍。该项目的中心假设是，Col/Hep涂层与可溶性干扰素协同工作，调节信号通路，调节增殖和免疫抑制特性。这一假说在很大程度上是基于初步数据表明，COL/HEP涂层：诱导碱性成纤维细胞生长因子(FGF2)的表达，减少干扰素的抗增殖作用，同时促进免疫调节细胞因子的分泌。具体目标是：(1)确定涂层与hMSCs中FGF2途径的激活之间的关系，及其与增殖的关系；(2)建立干扰素激活培养在COL/HEP涂层上的hMSCs的机制；(3)确定COL/HEP涂层在多大程度上保持在悬浮生物反应器中的微载体上。这个项目将通过将聚合物材料与生化信号相结合来产生一种增强hMSCs激活和治疗能力的技术，从而直接影响细胞制造领域。该项目由细胞和生化工程计划和既定的刺激竞争研究计划(EPSCoR)联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Delivery of Immobilized IFN-γ With PCN-333 and Its Effect on Human Mesenchymal Stem Cells

PCN-333 固定化 IFN-γ 的递送及其对人间充质干细胞的影响

• DOI: 10.1021/acsbiomaterials.2c01038
• 发表时间: 2023
• 期刊: ACS Biomaterials Science & Engineering
• 影响因子: 5.8
• 作者: Phipps, Josh;Haseli, Mahsa;Pinzon-Herrera, Luis;Wilson, Ben;Corbitt, Joshua;Servoss, Shannon;Almodovar, Jorge
• 通讯作者: Almodovar, Jorge

A comparative evaluation of layer‐by‐layer assembly techniques for surface modification of microcarriers used in human mesenchymal stromal cell manufacturing

• DOI: 10.1002/biot.202100605
• 发表时间: 2022-04
• 期刊: Biotechnology Journal
• 影响因子: 4.7
• 作者: Hemanta Timsina;J. McTyer;R. Rao;Jorge Almodóvar

Crosslinked layered surfaces of heparin and poly(L-lysine) enhance mesenchymal stromal cells behavior in the presence of soluble interferon gamma

肝素和聚（L-赖氨酸）的交联层状表面在可溶性干扰素γ存在下增强间充质基质细胞的行为

• DOI: 10.1159/000521609
• 发表时间: 2021
• 期刊: Cells Tissues Organs
• 影响因子: 2.7
• 作者: Haseli, Mahsa;Pinzon-Herrera, Luis;Almodovar, Jorge
• 通讯作者: Almodovar, Jorge