Rejuvenating the aged cell through epigenetic modulation: defining culture conditions to reverse mesenchymal stromal cell (MSC) ageing

通过表观遗传调节使衰老细胞恢复活力：定义培养条件以逆转间充质基质细胞 (MSC) 衰老

• 批准号: 2726008
• 金额: --
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2726008
• 关键词: Rejuvenating; aged; cell; through; epigenetic

Project rationale and importance: We have recently discovered epigenetic regulators that may be involved in MSC ageing. Our unpublished data using a short hairpin RNA (shRNA) library targeting 398 epigenetic enzymes indicates that silencing of specific epigenetic enzymes in aged/non-proliferating human MSCs (hMSCs) has the capacity to reverse growth arrest and re-establish cell proliferation. Interestingly, a large proportion of the identified epigenetic enzymes have associated small molecule (chemical/compound) modulators, which presents a unique opportunity to develop in vitro culture conditions that have the capacity to reverse hMSC ageing. Indeed, the reprogramming of somatic cells to pluripotency has taught us that at the cellular level it is possible to reset age to a 'ground state'. Careful manipulation of epigenetic state is also likely to make cells 'young again' without erasing their identity(4). This will ultimately lead to novel insights in how to reverse cell ageing and/or maintain cells in a youthful state, which will have significant impact and applications in regenerative medicine.Aim and objectives: This studentship will define the role of epigenetics in the ageing process of hMSCs, and create new technological advances towards the establishment of culture conditions to reverse cell ageing in vitro.Objective 1 To develop in vitro conditions with the capacity to modify hMSC ageing based on the control of epigenetic enzyme activity. Objective 2 To deliver a mechanistic understanding of the epigenetic control of hMSC ageing, hence identifying skeletal anti-ageing targets. Objective 3 To understand the heterogeneity of response to age reversal through epigenetic modulation by single cell RNA sequencing (scRNASeq).

项目原理和重要性：我们最近发现了可能参与MSC老化的表观遗传调节因子。我们使用靶向398种表观遗传酶的短发夹RNA（shRNA）文库的未发表数据表明，在老化/非增殖的人MSC（hMSC）中沉默特定的表观遗传酶具有逆转生长停滞和重建细胞增殖的能力。有趣的是，大部分鉴定的表观遗传酶具有相关的小分子（化学/化合物）调节剂，这为开发具有逆转hMSC老化能力的体外培养条件提供了独特的机会。事实上，将体细胞重新编程为多能性告诉我们，在细胞水平上，将年龄重置为“基态”是可能的。对表观遗传状态的仔细操纵也可能使细胞“再次年轻”，而不会消除它们的身份（4）。这将最终导致如何逆转细胞衰老和/或保持细胞处于年轻状态的新见解，这将在再生医学中产生重大影响和应用。目的和目标：这个学生将定义表观遗传学在hMSCs衰老过程中的作用，目的：1.建立体外培养条件，具有基于表观遗传酶活性的控制来改变hMSC老化的能力的条件。目的2了解hMSC衰老的表观遗传调控机制，从而确定骨骼抗衰老靶点。目的3通过单细胞RNA测序（scRNASeq）研究表观遗传调控对年龄逆转反应的异质性。