Engineered Asymmetric Hydrogel for Muscle Stem Cell Polarity and Fate Specification

用于肌肉干细胞极性和命运规范的工程不对称水凝胶

基本信息

  • 批准号:
    10576960
  • 负责人:
  • 金额:
    $ 45.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Skeletal muscle stem cell (MuSC) transplantation is emerging as a promising strategy for treating muscle- associated trauma and diseases. However, MuSCs spontaneously lose their “stemness” and engraftment potential in conventional 2D culture, critically limiting their applicability for cell-based therapy. This inability to culture MuSCs further limits the employment of cell engineering strategies, such as ex vivo gene editing patient derived cells. Thus, there is a critical need for a strategy to maintain and expand therapeutically potent MuSC ex vivo long-term. To date, MuSC culture systems that recapitulate the asymmetric MuSC niche, consisting of myofiber and basal lamina, required to establish cellular polarity, support physiologic cell division, and guide fate specification, do not exist. The contribution of active mechanical forces in modulating MuSC polarity, division, and fate specification also remains overlooked. We believe that establishing MuSC polarity is a requirement for supporting long-term symmetric expansion ex vivo through biochemical and biophysical means. To this end, the proposed research will engineer an asymmetric designer platform for expanding self-renewing MuSCs ex vivo long-term by directing cellular polarity and fate specification. In Aim 1, we will identify minimally essential asymmetric cues for establishing MuSC polarity by engineering an asymmetric hydrogel. In Aim 2, we will determine the effects of biochemically promoting symmetric cell division on long-term expansion of MuSCs using the asymmetric hydrogel. Biochemical strategies to inhibit asymmetric division and to promote symmetric division to achieve ex vivo MuSC expansion will be tested. In Aim 3, we will determine the effects of dynamic biomechanical stretch on regulation of symmetric MuSC expansion using the asymmetric hydrogel. Mechanisms by which externally applied forces align mitotic spindle orientation and regulate cell division of polarized MuSCs will be tested. Successful outcomes of this research will not only develop a platform for expanding MuSCs for cell therapies by directing stem cell polarity and fate specification but also provide establish a new paradigm for harnessing stem cell polarity in cell-instructive biomaterials for regenerative medicine.
摘要 骨骼肌干细胞(MuSC)移植正在成为治疗肌肉萎缩症的一种有前途的策略。 相关的创伤和疾病。然而,MuSC自发地失去它们的“干性”和植入, 在传统的2D培养中的潜力,严重限制了它们对基于细胞的治疗的适用性。这种无法 培养MuSC进一步限制了细胞工程策略的使用,例如离体基因编辑患者, 衍生细胞因此,迫切需要一种策略来维持和扩增治疗有效的MuSC。 离体长期。迄今为止,概括不对称MuSC生态位的MuSC培养系统,包括 肌纤维和基膜,需要建立细胞极性,支持生理细胞分裂,并引导 命运规范,不存在。主动机械力在调节MuSC极性中的贡献, 分裂和命运规范也仍然被忽视。我们认为,建立MuSC极性是一个 通过生物化学和生物物理手段支持离体长期对称扩增的要求。 为此,本研究将设计一个非对称的设计平台,用于扩展自我更新 通过指导细胞极性和命运特化,离体长期培养MuSC。在目标1中,我们将最低限度地识别 通过工程化非对称水凝胶建立MuSC极性的基本非对称线索。在目标2中, 将确定生物化学促进对称细胞分裂对MuSC长期扩增的影响 使用不对称水凝胶。抑制不对称分裂和促进对称分裂的生化策略 将测试分离以实现离体MuSC扩增。在目标3中,我们将确定动态 生物力学拉伸对使用不对称水凝胶调节对称MuSC扩张的影响。 外部作用力使有丝分裂纺锤体定向并调节细胞分裂的机制 将测试极化的MuSC。这项研究的成功成果不仅将为开发一个平台, 通过指导干细胞极性和命运特化来扩增用于细胞疗法的MuSC, 建立了一个新的范例,利用细胞指导性生物材料中的干细胞极性, 药

项目成果

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Woojin Han其他文献

Woojin Han的其他文献

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{{ truncateString('Woojin Han', 18)}}的其他基金

Diversity Supplement for: Engineered Asymmetric Hydrogel for Muscle Stem Cell Polarity and Fate Specification
多样性补充:用于肌肉干细胞极性和命运规范的工程不对称水凝胶
  • 批准号:
    10807823
  • 财政年份:
    2023
  • 资助金额:
    $ 45.54万
  • 项目类别:
Engineered Asymmetric Hydrogel for Muscle Stem Cell Polarity and Fate Specification
用于肌肉干细胞极性和命运规范的工程不对称水凝胶
  • 批准号:
    10405716
  • 财政年份:
    2022
  • 资助金额:
    $ 45.54万
  • 项目类别:
Notch-Modulatory Hydrogel for Dystrophic Muscle Stem Cell Rejuvenation and Expansion
用于营养不良性肌肉干细胞复兴和扩张的缺口调节水凝胶
  • 批准号:
    10629737
  • 财政年份:
    2022
  • 资助金额:
    $ 45.54万
  • 项目类别:
Synthetic hydrogel for satellite cell delivery to the dystrophic diaphragm
用于将卫星细胞递送至营养不良隔膜的合成水凝胶
  • 批准号:
    9901554
  • 财政年份:
    2018
  • 资助金额:
    $ 45.54万
  • 项目类别:

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