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
- 来源:
- 关键词:AccelerationAcuteAdultAgingAntibodiesBasal laminaBase SequenceBasic ScienceBindingBiologicalCell CompartmentationCell CycleCell NucleusCell TherapyCell TransplantationCell membraneCell surfaceCellsCharacteristicsChemicalsChromatinCommunitiesDNADataDedicationsDegenerative DisorderDiseaseDuchenne muscular dystrophyDystrophinEngraftmentEphrin-A5EphrinsEpigenetic ProcessExtracellular DomainFailureFamilyFrequenciesFundingFunding MechanismsGene ExpressionGene Expression ProfilingGenesGoalsGrowthHalf-LifeHomeostasisHumanIn VitroIndividualInjuryLabelLifeMediatingMethodsMitogensMolecularMusMuscleMuscle FibersMuscle functionMuscle satellite cellMyoD ProteinMyoblastsNatural regenerationNeuromuscular DiseasesPathologyPatient IsolationPatientsPhenotypePopulationPositioning AttributeProcessProliferatingPropertyProteinsRNARefractoryReproducibilityResearch PersonnelResistanceRestSerumSignaling MoleculeSkeletal Muscle Satellite CellsSourceSpecificitySpeedStructureTechniquesTechnologyTestingTherapeuticTherapeutic UsesTissuesTranslational ResearchTraumaUncertaintyadult stem cellaptamercostcost effectivecost effectivenessdensityextracellulargenetic manipulationimmunogenicityin vivoin vivo engraftmentinhibitorinjuredmuscle formmuscle regenerationnovelpostnatalprecursor cellpreventprogenitorproliferation potentialreceptorrepairedresponse to injurysatellite cellself-renewalskeletal muscle growthsmall moleculestem cell populationstem cellssuccesstimelinetooltranscription factortranslational applicationstranslational potentialvolumetric muscle loss
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
因为分化的、有功能的肌纤维中的所有细胞核都永久地退出了细胞周期,
当需要组织生长、修复或再生时,细胞群充当新细胞核的来源。卫星
在体内平衡期间,细胞处于夹在细胞膜之间的静止、非增殖状态
和分化的肌纤维的基底层。在这种状态下,它们表达卫星干细胞转录,
Pax 7因子,但几乎没有MyoD家族的转录因子。为了应对受伤或疾病,卫星
细胞被激活以重新进入细胞周期,上调MyoD和其他肌原性转录因子,
作为成肌细胞扩展以产生新的肌源性细胞,然后致力于终末分化并融合成新的
或现有的肌纤维。通过尚不清楚的机制,一部分卫星细胞后代
将重新进入静止状态并重新填充干细胞库。这个过程是快速和高效的,
并且在大多数情况下足以在整个生命中维持肌肉质量和功能。但如果票数
肌肉退行性疾病,如杜氏肌营养不良症或大面积创伤,
肌肉体积损失,内源性卫星细胞不足或不能修复肌肉,导致
长期病理学该领域的一个长期目标是分离患者或供体来源的卫星细胞
并离体扩增它们(可能与诸如肌营养不良蛋白基因的修复等操作相一致)
然后在治疗上移植它们,然而这种方法还没有取得很好的成功。一个主要
障碍是难以在体外维持卫星细胞及其后代处于增殖祖细胞状态:
即使在高促分裂原条件下,它们也倾向于终末分化,甚至那些
保持增殖性的细胞在很大程度上失去了它们的干细胞特性(例如,在体内作为卫星细胞自我更新的能力)。我们
有令人兴奋的新数据表明,在缺乏细胞表面信号分子肝配蛋白-A5的情况下,
成肌细胞不仅不会致力于终末分化,而且当在高密度下生长时,
退出细胞周期并表达高水平的Pax 7,因此在至少两个关键方面类似于静止的卫星细胞。
个方面当在低密度下再传代时,这些细胞将重新进入细胞周期并再次扩增,而不发生细胞周期性改变。
致力于终端差异化。为了将这一结果转化为潜在的翻译应用,我们
我建议尝试瞬时和可逆地抑制(而不是删除)肝配蛋白-A5,使成肌细胞
在培养中扩增而不损失分化,并且理想地增强移植时的干细胞特性。
我们选择开发RNA适体作为肝配蛋白-A5抑制剂,以利用适体的
结合的高特异性、无免疫原性、额外化学官能化的可能性,以及
速度和成本效益。如果成功,这项技术有可能大大提高
推进DMD和体积肌肉损失的细胞疗法,并通过允许
研究人员希望在延长的培养期内产生大量的祖细胞。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Dawn D Cornelison其他文献
Dawn D Cornelison的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 17.19万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 17.19万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 17.19万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 17.19万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 17.19万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 17.19万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 17.19万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 17.19万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 17.19万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 17.19万 - 项目类别: