Cyclical endometrial repair and regeneration: Molecular mechanisms, diseases, and therapeutic interventions

Abstract

The endometrium is a unique human tissue with an extraordinary ability to undergo a hormone-regulated cycle encompassing shedding, bleeding, scarless repair, and regeneration throughout the female reproductive cycle. The cyclical repair and regeneration of the endometrium manifest as changes in endometrial epithelialization, glandular regeneration, and vascularization. The mechanisms encompass inflammation, coagulation, and fibrinolytic system balance. However, specific conditions such as endometriosis or TCRA treatment can disrupt the process of cyclical endometrial repair and regeneration. There is uncertainty about traditional clinical treatments' efficacy and side effects, and finding new therapeutic interventions is essential. Researchers have made substantial progress in the perspective of regenerative medicine toward maintaining cyclical endometrial repair and regeneration in recent years. Such progress encompasses the integration of biomaterials, tissue-engineered scaffolds, stem cell therapies, and 3D printing. This review analyzes the mechanisms, diseases, and interventions associated with cyclical endometrial repair and regeneration. The review discusses the advantages and disadvantages of the regenerative interventions currently employed in clinical practice. Additionally, it highlights the significant advantages of regenerative medicine in this domain. Finally, we review stem cells and biologics among the available interventions in regenerative medicine, providing insights into future therapeutic strategies.

Keywords: biomaterial; endometrial repair; endometrium regeneration; menstrual cycle; regenerative medicine; tissue engineering scaffolds.

FIGURE 1

Schematic diagram on the interaction among coagulation, inflammation, and fibrinolytic systems in endometrial repair and regeneration. In endometrial repair and regeneration, upregulation of cytokine levels activates the NF‐κB signaling pathway, which ultimately leads to an increase in the expression of plasminogen activator inhibitor (PAI‐1), thereby inhibiting the activity of the fibrinolytic system. At the same time, if the balance between tPA and PAI‐1 is disrupted after sudden acute injury to the endometrium, it will lead to fibrin leakage and persistent fibrin aggregation.

FIGURE 2

Diseases and clinical interventions of cyclical endometrial repair and regeneration. (A) endometrial infection, (B) gynecological surgery, and (C) mycobiome dysbiosis, are the main causes of infection of microorganisms. Abnormal regenerative diseases include abnormal fibroplasia, abnormal smooth muscle proliferation, and abnormal endometrial growth. The resolution of their postoperatively induced intrauterine adhesions is (D) TCRA. Measures to promote endometrial repair and regeneration is followed by (E) intrauterine device (IUD), (F) intrauterine suitable balloons (ISBs), (G) hyaluronic acid hydrogel, (H) amniotic membrane transplantation (AMT), (I) uterine scaffolds to reserve the space of the uterus, and (J) drugs stimulating endometrial growth.

FIGURE 3

Scaffolds/hydrogels encapsulate therapeutics such as estrogen, cytokine, stem cells, or biologics to perform endometrial repair in rats.

FIGURE 4

Experimental protocols for preparing and testing HA/Abs hydrogels (A and C), a hydrogel system that expresses multiple therapeutic effects and effectively promotes endometrial regeneration and vascular regeneration to prevent adhesions from occurring. (B) Staining treatment 12 d after different treatments. Black dashed boxes indicate that the following image is shown at a higher magnification. (D) (n = 11) and endometrial glands (E) (n = 11) in (B). (F) Masson's trichrome staining scores for uteri under different treatments for 12 d (n = 11). **p < 0.01. Reprinted with permission from Ref. , Copyright 2022 Bioactive Materials.

FIGURE 5

Characterization of CS/UC‐MSCs (A) and effects of different treatments on endometrial regeneration and collagen remodeling (B and C). (A) A1–A6, characterization of CS/UC‐MSCs. (A and A4) Macroscopic observation of CS (A) and CS/UC‐MSCs (A4). (A2 and A5) HE staining of CS (A2) and CS/UC‐MSCs (A5). (A3 and A6) SEM images of CS (A3) and CS/UC‐MSCs (A6). (B) HE staining of uteri after different treatments for 15 days (B1–B4), 30 days (B5–B8), and 60 days (B9–B12) in the sham group (sham) (B1, B5, and B9), the natural repair group (NR) (B2, B6, and B10), the CS group (CS) (B3, B7, and B11) and the CS/UC‐MSCs group (CS/UC‐MSCs) (B4, B8, and B12). Inserts are the corresponding overview pictures with lower magnification and the magnified regions are marked with black squares. (b) Statistical analysis of endometrial thickness after different treatments for 15 days, 30 days and 60 days. (C) Collagen staining of uteri using Masson trichrome after different treatments for 15 days (C1–C4), 30 days (C5–C8) and 60 days (C9–C12) in the sham group (sham) (C1, C5, and C9), the natural repair group (NR) (C2, C6, and C10), the CS group (CS) (C3, C7, and C11) and the CS/UC‐MSCs group (CS/UC‐MSCs) (C4, C8, and C12). Inserts are the corresponding overview pictures with lower magnification and the magnified regions are marked with black squares. (c) Statistical analysis of the percentages of collagen positive staining after different treatments for 15 days, 30 days, and 60 days. (D) Reproductive outcomes over 60 days following different treatments. (a, p < 0.01 NR group versus CS/UC‐MSCs group. b, p < 0.01 CS group versus CS/UC‐MSCs group. c, p < 0.01 NR group versus CS/UC‐MSCs group. d, p > 0.05 CS group versus CS/UC‐MSCs group). Reprinted with permission from Ref. , Copyright 2019 Elsevier Science & Technology Journals.