Department of Biological Sciences, University of Cyprus, 1 University Avenue, 2109, Aglandjia, Nicosia, Cyprus.
Department of Biological Sciences, University of Cyprus, 1 University Avenue, 2109, Aglandjia, Nicosia, Cyprus.
Biochem Biophys Res Commun. 2021 Dec 20;584:66-72. doi: 10.1016/j.bbrc.2021.11.007. Epub 2021 Nov 5.
In the adult uterus of mice, rats and humans, the initially closely packed muscle bundles of the inner myometrium (muscular tissue that encircles the endometrium where the conceptus implants) undergo a pregnancy-induced dispersal that is clinically significant and hypothesized to regulate important pregnancy events. However, where, when and how this dispersal occurs, what its functions are, as well as its spatial relationship to the mouse metrial gland/mesometrial lymphoid aggregate of pregnancy (MG/MLAp), are unknown. The MG/MLAp, is a pregnancy-induced uterine structure required for successful rodent pregnancy located mesometrial to (above) the decidua basalis (pregnancy-modified mesometrial endometrium) and defined by its accumulation of maternal lymphocytes known as uterine Natural Killer (uNK) cells. To begin to understand how mouse inner myometrium dispersal (IMD) occurs, we spatiotemporally described it by observing the distribution of its muscle bundles and measuring their volume fraction (VF), as well as the VF of uNKs and stromal cells of inner myometrium. We discovered that (a) IMD (defined as reduction in VF of inner myometrium muscle bundles) is restricted to the mesometrial half of the uterus, is first evident at Embryonic day (E) 5.5 (early postimplantation) but not at E3.5 (preimplantation), further increases between E6.5 and E7.5 and remains unchanged from E7.5 to E10.5, (b) IMD initiation (observed between E3.5 and E5.5) occurs in the absence of uNKs and is associated with VF increases of pre-existing inner myometrium stromal cells and (c) the IMD observed between E6.5 and E7.5 is not associated with VF increases of uNKs or stromal cells. To get functional clues about IMD, we examined whether stromal cells between the dispersed muscle bundles undergo decidualization (important for correct fetomaternal interactions) and provide evidence that they do by E10.5, based on their production of Desmin (decidualization marker). Lastly, we examined whether mouse MG/MLAp only comprises the dispersed inner myometrium or additionally includes the mesometrial triangle (a triangular-like area mesometrial to the inner myometrium at the mesometrium-uterus attachment site), as is the case in rats. Our data supports that the dispersed inner myometrium is the only tissue that makes up the mouse MG/MLAp. In conclusion, we provide novel cellular and spatiotemporal insights about IMD that will contribute to understanding its mechanism and function and allow more informed inter-species comparisons about this process.
在成年小鼠、大鼠和人类的子宫中，最初紧密排列的内子宫肌（环绕着胚胎着床的子宫内膜的肌肉组织）经历了妊娠诱导的分散，这在临床上具有重要意义，并被假设调节着重要的妊娠事件。然而，这种分散发生在哪里、何时发生以及如何发生，其功能是什么，以及它与小鼠蜕膜腺/子宫系膜淋巴聚集（MG/MLAp）的空间关系是什么，目前还不清楚。MG/MLAp 是一种妊娠诱导的子宫结构，位于底蜕膜（妊娠修饰的子宫系膜内膜）上方的子宫系膜（mesometrial），对于成功的啮齿动物妊娠是必需的，其特征是积累了称为子宫自然杀伤（uNK）细胞的母体淋巴细胞。为了开始了解小鼠内子宫肌分散（IMD）是如何发生的，我们通过观察其肌肉束的分布并测量其体积分数（VF），以及 uNK 细胞和内子宫肌基质细胞的 VF，来时空描述它。我们发现：（a）IMD（定义为内子宫肌束 VF 的减少）仅限于子宫系膜侧，最早在胚胎期（E）5.5 天（着床后早期）可见，但在 E3.5 天（着床前）不可见，在 E6.5 天至 E7.5 天之间进一步增加，在 E7.5 天至 E10.5 天之间保持不变；（b）IMD 起始（在 E3.5 天至 E5.5 天之间观察到）发生在 uNK 细胞不存在的情况下，与预先存在的内子宫肌基质细胞的 VF 增加有关；（c）在 E6.5 天至 E7.5 天之间观察到的 IMD 与 uNK 细胞或基质细胞的 VF 增加无关。为了获得关于 IMD 的功能线索，我们检查了分散的肌肉束之间的基质细胞是否经历了蜕膜化（对正确的胎母相互作用很重要），并根据 E10.5 天时它们产生的 Desmin（蜕膜化标志物）提供了证据。最后，我们检查了小鼠 MG/MLAp 是否仅由分散的内子宫肌组成，或者是否还包括子宫系膜三角（子宫系膜附着部位的内子宫系膜侧的三角形区域），就像大鼠一样。我们的数据支持这样一种观点，即分散的内子宫肌是构成小鼠 MG/MLAp 的唯一组织。总之，我们对内子宫肌分散提供了新的细胞和时空见解，这将有助于理解其机制和功能，并允许对这一过程进行更有根据的种间比较。
