Ex vivo expansion of skeletal muscle satellite cells

骨骼肌卫星细胞的离体扩增

基本信息

  • 批准号:
    10570269
  • 负责人:
  • 金额:
    $ 17.19万
  • 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:
    2022-02-10 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

SUMMARY Because all nuclei in differentiated, functional myofibers have permanently exited the cell cycle, the satellite cell population acts as a source of new nuclei when tissue growth, repair, or regeneration is required. Satellite cells during homeostasis rest in a quiescent, nonproliferative state sandwiched between the cell membrane and the basal lamina of a differentiated myofiber. In this state they express the satellite stem cell transcription factor Pax7 but little to no transcription factors of the MyoD family. In response to injury or disease, satellite cells are activated to re-enter the cell cycle, upregulate MyoD and other myogenic transcription factors, and expand as myoblasts to generate new myogenic cells, then commit to terminal differentiation and fuse into new or existing myofibers. Through mechanisms that are not yet well understood a fraction of satellite cell progeny will re-enter the quiescent state and repopulate the stem cell pool. This process is rapid and highly effective, and in most cases is sufficient to maintain muscle mass and function throughout life. However, in the case of muscle degenerative diseases such as Duchenne's muscular dystrophy or massive trauma leading to volumetric muscle loss, endogenous satellite cells are insufficient or unable to repair the muscle leading to long-term pathology. A longstanding goal in the field has been isolating patient- or donor-derived satellite cells and expanding them ex vivo (potentially in concert with manipulations such as repair of the dystrophin gene) then engrafting them therapeutically, however this approach has not yet met with good success. One major hurdle is the difficulty of maintaining satellite cells and their progeny in a proliferative progenitor state in vitro: they tend to commit to terminal differentiation even under high-mitogen conditions, and even those cells that remain proliferative largely lose their stem cell character (e.g., ability to self-renew as satellite cells in vivo). We have exciting new data showing that in the absence of the cell surface signaling molecule ephrin-A5, myoblasts will not only not commit to terminal differentiation but they will, when grown at high densities, instead exit the cell cycle and express high levels of Pax7, thus resembling quiescent satellite cells in at least two key respects. When repassaged at low density, these cells will re-enter the cell cycle and expand again without committing to terminal differentiation. To leverage this result into a potential translational application, we propose to attempt to transiently and reversibly inhibit (rather than delete) ephrin-A5, to allow myoblast expansion in culture without loss to differentiation and ideally to enhance stem cell character on engraftment. We have chosen to develop RNA aptamers as ephrin-A5 inhibitors in order to take advantage of aptamers' high specificity of binding, absence of immunogenicity, potential for additional chemical functionalization, and speed and cost-effectiveness to generate. If successful, this technique has the potential to significantly advance cell-based therapies for DMD and volumetric muscle loss and to accelerate basic science by allowing researchers to generate of large numbers of progenitor cells over extended culture periods.
总结

项目成果

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Dawn D Cornelison其他文献

Dawn D Cornelison的其他文献

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{{ truncateString('Dawn D Cornelison', 18)}}的其他基金

Ex vivo expansion of skeletal muscle satellite cells
骨骼肌卫星细胞的离体扩增
  • 批准号:
    10390539
  • 财政年份:
    2022
  • 资助金额:
    $ 17.19万
  • 项目类别:
EphA7 promotes contact-dependent myogenesis
EphA7促进接触依赖性肌生成
  • 批准号:
    10219157
  • 财政年份:
    2020
  • 资助金额:
    $ 17.19万
  • 项目类别:
EphA7 promotes contact-dependent myogenesis
EphA7促进接触依赖性肌生成
  • 批准号:
    10410527
  • 财政年份:
    2020
  • 资助金额:
    $ 17.19万
  • 项目类别:
EphA7 promotes contact-dependent myogenesis
EphA7促进接触依赖性肌生成
  • 批准号:
    10672896
  • 财政年份:
    2020
  • 资助金额:
    $ 17.19万
  • 项目类别:
Ephrin-A3 Specifies Slow Muscle Fiber Type
Ephrin-A3 指定慢肌纤维类型
  • 批准号:
    8923146
  • 财政年份:
    2014
  • 资助金额:
    $ 17.19万
  • 项目类别:
Ephrin-A3 specifies slow muscle fiber type
Ephrin-A3 指定慢肌纤维类型
  • 批准号:
    8810472
  • 财政年份:
    2014
  • 资助金额:
    $ 17.19万
  • 项目类别:
Soluble Motogens and Chemoattractants from Damaged Muscle
受损肌肉中的可溶性促动力剂和化学引诱剂
  • 批准号:
    8383029
  • 财政年份:
    2012
  • 资助金额:
    $ 17.19万
  • 项目类别:
Soluble Motogens and Chemoattractants from Damaged Muscle
受损肌肉中的可溶性促动力剂和化学引诱剂
  • 批准号:
    8500217
  • 财政年份:
    2012
  • 资助金额:
    $ 17.19万
  • 项目类别:
Molecular Mechanisms Regulating Motility and Migration of Muscle Satellite Cells
调节肌肉卫星细胞运动和迁移的分子机制
  • 批准号:
    7907839
  • 财政年份:
    2009
  • 资助金额:
    $ 17.19万
  • 项目类别:
Molecular mechanisms regulating motility and migration of muscle satellite cells
调节肌肉卫星细胞运动和迁移的分子机制
  • 批准号:
    7572440
  • 财政年份:
    2009
  • 资助金额:
    $ 17.19万
  • 项目类别:

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