ΔNp63 maintains the fidelity of the myoepithelial cell lineage and directs cell differentiation programs in the murine salivary gland.
ΔNp63 maintains the fidelity of the myoepithelial cell lineage and directs cell differentiation programs in the murine salivary gland.
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DOI：
10.1038/s41418-022-01101-0
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发表时间：
2023-02
影响因子：
12.4
通讯作者：
Romano, Rose-Anne
中科院分区：
文献类型：
--
作者：
Song, Eun-Ah Christine;Che, Monika;Osinski, Jason;Smalley, Kirsten;Horeth, Erich;Sinha, Satrajit;Romano, Rose-Anne
唾液腺由具有不同谱系和功能特征的几种上皮细胞类型组成，所述上皮细胞类型通过驻留干细胞和祖细胞的定向分化程序建立。我们已经表明，Δ Np 63，一个关键的转录调节因子的干/祖细胞，是丰富的基底和肌上皮细胞（MEC）的人口和Δ Np 63阳性细胞保持所有的后裔上皮细胞谱系的成年小鼠唾液腺（mSG）。尽管已经证明了Δ Np 63在驱动mSG中更广泛的上皮细胞命运和身份方面的关键作用，但Δ Np 63如何在MEC群体的定型和分化中特异性地发挥作用尚不清楚。使用允许细胞追踪的多个遗传小鼠模型，我们表明Δ Np 63在维持和更新MEC中至关重要，部分通过Acta 2基因表达的转录调节，Acta 2基因表达是该细胞群体的定义标记。我们证明，在成人mSG稳态期间，Δ Np 63富集的MEC作为双能祖细胞发挥功能，不仅维持MEC群体，而且维持明显不同的导管细胞谱系。这一过程的保真度取决于Δ Np 63的表达，因为MEC特异性消融Δ Np 63导致MEC分化改变，并影响细胞可塑性，导致闰管和腺泡细胞的异常分化。相比之下，我们发现MEC对严重损伤后导管和腺泡细胞再生的贡献与Δ Np 63无关。我们的观察提供了新的见解细胞机制驱动MEC的命运选择和分化程序的背景下，唾液腺稳态和响应损伤和再生。从长远来看，这些发现对通过基于干细胞的方法更好地治疗唾液腺功能障碍具有重要意义。
Salivary glands consist of several epithelial cell types of distinct lineages and functional characteristics that are established by directed differentiation programs of resident stem and progenitor cells. We have shown that ΔNp63, a crucial transcriptional regulator of stem/progenitor cells, is enriched in both the basal and myoepithelial cell (MEC) populations and that ΔNp63 positive cells maintain all the descendent epithelial cell lineages of the adult mouse salivary glands (mSGs). Although this pivotal role of ΔNp63 in driving the broader epithelial cell fate and identity in the mSG has been demonstrated, how ΔNp63 functions specifically in the commitment and differentiation of the MEC population is less understood. Using multiple genetic mouse models that allow for cell tracing, we show that ΔNp63 is critical in maintaining and renewing MECs, in part through the transcriptional regulation of Acta2 gene expression, a defining marker of this cell population. We demonstrate that during adult mSG homeostasis, ΔNp63 enriched MECs function as bipotent progenitor cells that maintain not only the MEC population, but also the distinctly different ductal cell lineages. The fidelity of this process is dependent on ΔNp63 expression, since MEC-specific ablation of ΔNp63 results in altered MEC differentiation and affects cellular plasticity resulting in aberrant differentiation of the intercalated ducts and acinar cells. In contrast, we find that the contribution of MECs to ductal and acinar cell regeneration following severe injury is independent of ΔNp63. Our observations offer new insights into cellular mechanisms driving MEC fate choices and differentiation programs in the context of salivary gland homeostasis and in response to injury and regeneration. Long term, these findings have implications for better treatment of salivary gland dysfunction through stem cell-based approaches.
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影响因子：
2.4
作者：
Amano O;Mizobe K;Bando Y;Sakiyama K
通讯作者：
Sakiyama K
影响因子：
3.6
作者：
Haaksma, Carol J.;Schwartz, Robert J.;Tomasek, James J.
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影响因子：
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Emmerson E;May AJ;Berthoin L;Cruz-Pacheco N;Nathan S;Mattingly AJ;Chang JL;Ryan WR;Tward AD;Knox SM
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影响因子：
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Ovitt, Catherine E.
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作者：
May, Alison J.;Cruz-Pacheco, Noel;Knox, Sarah M.
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