In preprints: the extracellular matrix influences primordial germ cell behavior Free

A recent preprint by Goodwin and colleagues reveals an intricate PGC-ECM interaction through investigating the mechanobiological regulation of mouse PGCs during migration (Goodwin et al., 2025 preprint). During mouse embryogenesis, PGCs originate from the posterior epiblasts at around embryonic day (E) 6.5. They migrate through mesoderm to endoderm at around E7.5, and exit from hindgut endoderm to migrate through the mesentery to settle in the gonadal ridges at around E9.5 (Richardson and Lehmann, 2010). Goodwin and colleagues employ dynamic and quantitative analysis of embryonic imaging, combined with atomic force microscopy, to describe how ECM biophysical cues orchestrate the migration of mouse PGCs. They demonstrate that between E7.5 and E9.5, PGCs consistently rely on actin-rich protrusions to migrate along the pathways enriched in ECM components, including collagen IV, fibronectin and laminin. Interestingly, Lamb1 proteins and mRNAs are detected in migrating PGCs, indicating that PGCs participate in the construction of the ECM-rich migratory micro-environment by secreting laminin.

Crucial biomechanical transitions occur at the endodermal interface. The gradual compaction of the basement membrane (BM) during embryonic development imposes a selective barrier, which requires significant deformation of PGCs and their nuclei to break through the BM and enter the mesentery. Notably, shape-shifting adaptations in migrating PGCs also result in cell rupture and DNA damage, which are more severe with increasing confinement. In turn, PGCs help cope with these stresses by depleting nuclear lamina proteins to remodel the nuclear lamina and promote nuclear envelope invagination. This suggests that mechanical properties of the ECM, such as rigidity and spatial confinement, directly affect the migratory capacity and genetic stability of PGCs, which balance the generation of migratory forces and genomic protection through interactions with the ECM and self-regulation.

Ichikawa and colleagues focus on how the ECM affects the proliferation and self-renewal of chicken PGCs under in vitro culture conditions (Ichikawa et al., 2025 preprint). Unlike mammals, chicken PGCs could be cultured for extended periods in vitro, making them an ideal model for studying self-renewal and identity maintenance (Van De Lavoir et al., 2006; Whyte et al., 2015). Ichikawa and colleagues reveal that integrin signaling plays a crucial role in sustaining PGC self-renewal. When agarose gel coatings are applied to reduce PGC adhesion or when the integrin signaling pathway is inhibited, the proliferation ability of PGCs significantly decreases, highlighting the importance of the PGC-matrix interaction for their proliferation. Conversely, the use of a proliferation medium supplemented with fibronectin enhances PGC adhesion, and this excessive PGC-ECM interaction results in partial epithelial-mesenchymal transition of PGCs and triggers PGC differentiation towards somatic cell lineages. These findings underscore the dual role of ECM signals in PGC self-renewal: moderate ECM signaling supports proliferation and maintenance of an undifferentiated state, whereas excessive signaling triggers differentiation. Thus, the regulation of ECM signal levels is crucial for preserving the self-renewal ability of PGCs and preventing their unnecessary differentiation.

Overall, both studies underscore the pivotal role of the ECM in regulating PGC behavior, revealing its dual role in PGC migration and self-renewal, and demonstrating how mechanical properties and biochemical signals together influence the development of PGCs (Goodwin et al., 2025 preprint; Ichikawa et al., 2025 preprint). Goodwin and colleagues highlight that PGCs migrate within the embryo during development through interactions with the basement membrane and other ECM components. While the ECM guides PGC migration, it also exerts mechanical pressure on the cells, thereby affecting their nuclear morphology and genetic stability. On the other hand, Ichikawa and colleagues explore the role of the ECM in maintaining PGC identity and self-renewal from the perspective of in vitro culture, particularly through integrin-mediated signaling, to highlight that balanced ECM regulation is essential to prevent excessive differentiation of PGCs. Despite differential research focuses, both studies collectively reveal that the ECM not only provides physical support during PGC migration, but also regulates PGC proliferation, differentiation and identity maintenance via biochemical signals, offering a new perspective to examine PGC-matrix interactions.

As described in the above studies, the ECM plays several crucial roles in PGC migration, self-renewal and fate maintenance. In a constrained migration environment, PGCs respond to mechanical stress by altering nuclear morphology and membrane structure to protect themselves from DNA damage (Goodwin et al., 2025 preprint). This suggests that PGC migration is not merely a passive response process, but also an active adaptive behavior. PGCs constantly adjust their actions to accommodate changes in the extracellular environment. Notably, some migrating PGCs undergo cell rupture and death (Goodwin et al., 2025 preprint), indicating that migration not only facilitates the movement of PGCs from the hindgut to the gonads to create space for the final orientation and gene reprogramming, but may also serve as a selection process for environmental adaptability.

Additionally, the ECM may contain growth factors that promote PGC migration and orientation by regulating receptor activation (De Felici and Pesce, 1994; Taipale and Keski-Oja, 1997). ECM components, such as fibronectin and laminin, provide structural support for PGCs, guiding them towards the gonads through specific signaling pathways. However, the precise mechanisms through which the ECM interacts with chemokines or growth factors to initiate and guide PGC migration remain an important focus for further investigation. Another key aspect of PGC migration is the maintenance of cell fate. Interestingly, avian PGCs express matrix components themselves, and mouse PGCs also secrete ECM components (Goodwin et al., 2025 preprint; Huss et al., 2019). This conservative self-secretion of ECM components across species may represent an active regulatory mechanism that maintains ECM homeostasis during migration in vivo, thereby resisting somatic cell fate. Moreover, the balanced regulation of the ECM is crucial for the in vitro culture of chicken PGCs, which remains the only established in vitro culture system for PGCs. Future studies focusing on ECM-PGC interactions will facilitate the establishment of a long-term in vitro culture system for PGCs from other organisms, including humans.

In conclusion, how the ECM regulates PGC migration path and localization in the embryo through specific growth factors and signaling pathways warrants deeper investigation. Additionally, how to precisely regulate the physical and biochemical properties of the ECM in in vitro PGC culture systems to maintain PGC proliferation and undifferentiated states will be an important focus for future research. These investigations are not only expected to provide a new theoretical basis for regenerative medicine and gonadal cell therapy, but may also offer innovative strategies and technical support to improve reproductive health.