Intrauterine botulinum toxin A administration promotes endometrial regeneration mediated by IGFBP3-dependent OPN proteolytic cleavage in thin endometrium

Lee, Danbi; Ahn, Jung Yong; Koo, Hwa Seon; Kang, Youn‐Jung

doi:10.1007/s00018-022-04684-6

Cited by 5 publications

(3 citation statements)

References 66 publications

(87 reference statements)

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“…Further studies found that intrauterine BoTA injection improved the endometrial environment in mice with TE by increasing endometrial tolerance and angiogenesis via the regulatory effect of IGFBP3 on hydrolytic cleavage of OPN proteins; these findings suggest BoTA as a potential therapeutic strategy for patients with TE. However, there is currently insufficient basis for clinical trials, and clinical validation is needed ( 45 ).…”

Section: Te Treatmentsmentioning

confidence: 99%

New advances in the treatment of thin endometrium

Wang,

Tang,

Teng

2024

Front. Endocrinol.

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Thin endometrium (TE) is defined as a mid-luteal endometrial thickness ≤7mm. TE can affect endometrial tolerance, leading to lower embryo implantation rates and clinical pregnancy rates, and is also associated with impaired outcomes from assisted reproductive treatment. Herein, we systematically review TE causes, mechanisms, and treatments. TE pathogenesis has multiple causes, with the endometrium becoming thinner with age under hormonal influence. In addition, uterine cavity factors are important, as the inflammatory environment may affect expressions of certain genes thereby inhibiting endometrial stromal cell proliferation and promoting apoptosis. Long-term oral contraceptive use or the use of ovulation-promoting drugs are also definite factors contributing to endometrial thinning. Other patients have primary factors, for which the clinical etiology remains unknown. The main therapeutic strategies available for TE are pharmacological (including hormonal and vasoactive drugs), regenerative medicine, intrauterine infusion of growth factor-granulocyte colony-stimulating factor, autologous platelet-rich plasma, and complementary alternative therapies (including traditional Chinese herbal medicine and acupuncture). However, the associated mechanisms of action are currently unclear. Clinical scholars have proposed various approaches to improve treatment outcomes in patients with TE, and are exploring the principles of efficacy, offering potentials for novel treatments. It is hoped that this will improve TE tolerance, increase embryo implantation rates, and help more couples with infertility with effective treatments.

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Section: Te Treatmentsmentioning

confidence: 99%

New advances in the treatment of thin endometrium

Wang,

Tang,

Teng

2024

Front. Endocrinol.

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“…Immunofluorescence staining was performed as previously described [33]. Briefly, CD31 (Abcam, UK), Ki67 (BD Biosciences, USA), E-CADHERIN (Santacruz, USA), CK14 (Abcam, UK), ER (GeneTex, USA), TOMM20 (Abcam, UK) and GFP (Santacruz, USA) was detected in fixed and paraffin embedded-endometrial tissue or organoids sections.…”

Section: Immunofluorescence and Microscopymentioning

confidence: 99%

“…Whole uteri were homogenized in Labozol (Cosmo, South Korea) and the complementary DNAs were synthesized as previously described [33]. RT-qPCR was performed on cDNA to assess the expression of genes of interest with SYBR Green (Enzynomics, South Korea).…”

Section: Quantitative Rt-pcr-based Analysis Of Mrna Expressionmentioning

confidence: 99%

Endometrial organoids: a reservoir of functional mitochondria for uterine repair

Hwang,

Lee,

Lee

et al. 2024

Theranostics

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Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility. Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established. Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment. The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium. The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta. To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium. Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice. Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids. Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium. Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS. Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.

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Evolution of biotechnological advances and regenerative therapies for endometrial disorders: a systematic review

Rodríguez-Eguren,

Bueno-Fernandez,

Gómez-Álvarez

et al. 2024

Human Reproduction Update

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BACKGROUND The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes. OBJECTIVE AND RATIONALE This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed. SEARCH METHODS A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches. OUTCOMES From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested. WIDER IMPLICATIONS Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis. REGISTRATION NUMBER https://osf.io/th8yf/

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Intrauterine botulinum toxin A administration promotes endometrial regeneration mediated by IGFBP3-dependent OPN proteolytic cleavage in thin endometrium

Cited by 5 publications

References 66 publications

New advances in the treatment of thin endometrium

New advances in the treatment of thin endometrium

Endometrial organoids: a reservoir of functional mitochondria for uterine repair

Evolution of biotechnological advances and regenerative therapies for endometrial disorders: a systematic review

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