Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells.
Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells.
复制标题
DOI：
10.1002/jcp.24680
复制
发表时间：
2015-01
影响因子：
5.6
通讯作者：
Van Wijnen, Andre J.
中科院分区：
文献类型：
--
作者：
Dudakovic, Amel;Camilleri, Emily T.;Lewallen, Eric A.;Mcgee-Lawrence, Meghan E.;Riester, Scott M.;Kakar, Sanjeev;Montecino, Martin;Stein, Gary S.;Ryoo, Hyun-Mo;Dietz, Allan B.;Westendorf, Jennifer J.;Van Wijnen, Andre J.
人脂肪间充质干细胞（AMSC）在血小板裂解物中生长是有前途的治疗性组织再生剂。在这里，我们调查了是否操纵表观遗传事件的临床相关的组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（SAHA）改变AMSC的分化。AMSC的多能性通过其分化为成骨、成软骨和成脂谱系的能力来验证。高通量RNA测序和RT-qPCR确定了人组蛋白脱乙酰酶（HDAC 1至HDAC 11和SIRT 1至SIRT 7）在AMSC中的差异表达。SAHA诱导组蛋白H3和H4的超乙酰化，刺激HDAC应答基因SLC 9A 3R 1/NHERF 1的蛋白质表达，并调节AKT/FOXO 1通路。在生物学上，SAHA干扰多能AMSC的成骨、成软骨和成脂谱系定型。从机制上讲，SAHA诱导的未定型AMSC分化潜能丧失与控制间充质或多能状态的主要转录因子表达的多种变化相关。我们认为，SAHA通过超乙酰化和关键转录因子通路的干扰破坏了未定型人类AMSC的多能表观遗传状态。此外，在血小板裂解物中生长的AMSC可以为筛选控制人间充质基质细胞生物命运的新HDAC抑制剂提供有用的生物学模型。
Human adipose-derived mesenchymal stromal cells (AMSCs) grown in platelet lysate are promising agents for therapeutic tissue regeneration. Here, we investigated whether manipulation of epigenetic events by the clinically relevant histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alters differentiation of AMSCs. The multipotency of AMSCs was validated by their ability to differentiate into osteogenic, chondrogenic and adipogenic lineages. High-throughput RNA sequencing and RT-qPCR established that human histone deacetylases (HDAC1 to HDAC11, and SIRT1 to SIRT7) are differentially expressed in AMSCs. SAHA induces hyper-acetylation of histone H3 and H4, stimulates protein expression of the HDAC-responsive gene SLC9A3R1/NHERF1 and modulates the AKT/FOXO1 pathway. Biologically, SAHA interferes with osteogenic, chondrogenic and adipogenic lineage commitment of multipotent AMSCs. Mechanistically, SAHA-induced loss of differentiation potential of uncommitted AMSCs correlates with multiple changes in the expression of principal transcription factors that control mesenchymal or pluripotent states. We propose that SAHA destabilizes the multi-potent epigenetic state of uncommitted human AMSCs by hyper-acetylation and perturbation of key transcription factor pathways. Furthermore, AMSCs grown in platelet lysate may provide a useful biological model for screening of new HDAC inhibitors that control the biological fate of human mesenchymal stromal cells.
登录
查看更多内容
影响因子：
4.8
作者：
Haberland, Michael;Carrer, Michele;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
20.3
作者：
Ng, Felicia;Boucher, Shayne;Tanavde, Vivek
通讯作者：
Tanavde, Vivek
影响因子：
4.8
作者：
Koç, ON;Day, J;Krivit, W
通讯作者：
Krivit, W
影响因子：
5.2
作者：
Kern, Susanne;Eichler, Hermann;Bieback, Karen
通讯作者：
Bieback, Karen
影响因子：
8.5
作者：
Lee, S.;Park, J-R.;Kang, K-S.
通讯作者：
Kang, K-S.