Introduction: The endometrium exhibits the ability to regenerate without
scarring after menstruation or parturition. Postpartum uterine repair occurs in a
unique environment, shaped by peripartum immune responses. However, the
mechanisms leading to healing or excessive fibrosis remain poorly understood.
This study aimed to evaluate the drastic postpartum changes and the involvement
of the immune milieu in the process of full wound regeneration.
Methods: Publicly available scRNA-seq data of human myometrium from nonpregnant
or postpartum day 7 individuals were analyzed. Allogenically mated and
virgin C57/BL6 female mice served as models for human postpartum healing.
Uterine tissues were analyzed by flow cytometry, immunohistochemistry,
immunofluorescence, and quantitative real-time polymerase chain reaction.
Results: Human myometrial scRNA-seq revealed a sustained upregulation of
immune responses in a context of degrowth of muscle components by
postpartum day 7. As shown in mice, the size of the myometrium rapidly
retracts. Particularly, the gradual resorption of the main site of leukocyte
infiltration during pregnancy and postpartum, the mesometrial triangle, grants
restoration of myometrial layers, dispersed during pregnancy to accommodate
the leucocyte aggregates and growing conceptus. This region, encircling the
lesions left by placental detachment, abundantly recruits macrophages that
remain CD206neg. This inflammatory reaction coincides with elevated levels of
Tnf, Il2, and Ifng, neovascularization, and cell death, and is balanced by increased
Il10 levels. CD8+ T cells also seeded the mesometrial triangle, along with
myofibroblasts surrounding the placental detachment clot until healing. This
immune response was confined to the mesometrial area by a collagen-rich
capsule. In turn, neighboring myometrial macrophages, largely expressing
CD206, expanded during early remodeling to retract at homeostasis.
Conclusion: In healthy postpartum uterus tissue, we identified the myometrium,
endometrium, and mesometrial triangle as distinct anatomical compartments
undergoing remodeling, each with unique yet interconnected processes. Within
these, the distribution of F4/80+CD206+ and F4/80+CD206neg macrophage
populations corresponded to different levels of tissue disruption. Inflammation, highly restricted by a collagen capsule and enhanced IL10, resolved to endorse
myometrium integrity. Whether these mechanisms safeguard the myometrium
from excessive immune responses, often linked to fibrosis, requires further
empirical investigation.