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维甲酸受体反向激动剂处理抑制人骨髓间充质干细胞肥大

Attenuation of Hypertrophy in Human MSCs via Treatment with a Retinoic Acid Receptor Inverse Agonist.

机构信息

Regensburg University Medical Center, Department of Trauma Surgery, 93053 Regensburg, Germany.

Regensburg University Medical Center, Laboratory of Experimental Trauma Surgery, Department of Trauma Surgery, 93053 Regensburg, Germany.

出版信息

Int J Mol Sci. 2020 Feb 20;21(4):1444. doi: 10.3390/ijms21041444.

DOI:10.3390/ijms21041444
PMID:32093330
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7073129/
Abstract

In vitro chondrogenically differentiated mesenchymal stem cells (MSCs) have a tendency to undergo hypertrophy, mirroring the fate of transient "chondrocytes" in the growth plate. As hypertrophy would result in ossification, this fact limits their use in cartilage tissue engineering applications. During limb development, retinoic acid receptor (RAR) signaling exerts an important influence on cell fate of mesenchymal progenitors. While retinoids foster hypertrophy, suppression of RAR signaling seems to be required for chondrogenic differentiation. Therefore, we hypothesized that treatment of chondrogenically differentiating hMSCs with the RAR inverse agonist, BMS204,493 (further named BMS), would attenuate hypertrophy. We induced hypertrophy in chondrogenic precultured MSC pellets by the addition of bone morphogenetic protein 4. Direct activation of the RAR pathway by application of the physiological RAR agonist retinoic acid (RA) further enhanced the hypertrophic phenotype. However, BMS treatment reduced hypertrophic conversion in hMSCs, shown by decreased cell size, number of hypertrophic cells, and collagen type X deposition in histological analyses. BMS effects were dependent on the time point of application and strongest after early treatment during chondrogenic precultivation. The possibility of modifing hypertrophic cartilage via attenuation of RAR signaling by BMS could be helpful in producing stable engineered tissue for cartilage regeneration.

摘要

体外分化的间充质干细胞 (MSCs) 有向肥大细胞转化的趋势，这反映了生长板中短暂“软骨细胞”的命运。由于肥大会导致骨化，这一事实限制了它们在软骨组织工程应用中的使用。在肢体发育过程中，视黄酸受体 (RAR) 信号对间充质祖细胞的细胞命运发挥着重要影响。虽然类视黄醇促进肥大，但 RAR 信号的抑制似乎是软骨分化所必需的。因此，我们假设用 RAR 反向激动剂 BMS204,493（进一步命名为 BMS）处理软骨分化的 hMSC 会减弱肥大。我们通过添加骨形态发生蛋白 4 诱导软骨前培养的 MSC 微球肥大。应用生理 RAR 激动剂视黄酸 (RA) 直接激活 RAR 途径进一步增强了肥大表型。然而，BMS 处理减少了 hMSC 中的肥大转化，表现在细胞大小、肥大细胞数量和组织学分析中胶原蛋白 X 沉积减少。BMS 的作用取决于应用的时间点，在软骨前培养早期处理时作用最强。通过 BMS 减弱 RAR 信号来修饰肥大软骨的可能性有助于产生用于软骨再生的稳定工程组织。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/7073129/b149a4bf1297/ijms-21-01444-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/7073129/ef680a40ebb6/ijms-21-01444-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/7073129/030179693265/ijms-21-01444-g003.jpg
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