Human Platelet-Rich Plasma Facilitates Angiogenesis to Restore Impaired Uterine Environments with Asherman’s Syndrome for Embryo Implantation and Following Pregnancy in Mice

Kim, Min Kyoung; Yoon, Jung Ah; Yoon, Sook Young; Park, Mira; Lee, Woo Sik; Lyu, Sang Woo; Song, Haengseok

doi:10.3390/cells11091549

Cited by 16 publications

(11 citation statements)

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“…A few studies have described the beneficial effect of adult PRP ( Kim et al , 2020 , 2022 ; Zhou et al , 2020 ) and commercialized hUC plasma ( de Miguel-Gómez et al. , 2021a ) in preclinical murine models of AS/EA, and have they reported findings similar to the ones presented herein, in terms of endometrial regeneration, augmented angiogenesis, cell proliferation and ability to achieve pregnancy.…”

Section: Discussionsupporting

confidence: 67%

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

Rodríguez-Eguren¹,

Miguel-Gómez²,

Francés-Herrero

et al. 2022

Human Reproduction Open

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STUDY QUESTION Can human umbilical cord platelet-rich plasma (hUC-PRP) efficiently treat endometrial damage and restore fertility in a preclinical murine model? SUMMARY ANSWER Local application of hUC-PRP promotes tissue regeneration and fertility restoration in a murine model of Asherman syndrome and endometrial atrophy (AS/EA). WHAT IS KNOWN ALREADY AS/EA are well-described endometrial pathologies that cause infertility, however, there are currently no gold standard treatments available. Recent reports have described the successful use of human platelet-rich plasma (hPRP) in reproductive medicine, and its regenerative potential is further enhanced using hUC-PRP, due to the ample growth factors and reduced pro-inflammatory cytokines in the latter. STUDY DESIGN, SIZE, DURATION hUC-PRP (n = 3) was processed, characterized, and delivered locally to endometrial damage in a murine model (n = 50). The hUC-PRP was either used alone or loaded into a decellularized porcine endometrium-derived extracellular matrix (EndoECM) hydrogel; endometrial regeneration, fertility outcomes and immunocompatibility were evaluated two weeks following treatment administration. PARTICIPANTS/MATERIALS, SETTING, METHODS Umbilical cord blood was obtained from women in childbirth. Endometrial damage (mimicking AS/EA) was induced using ethanol in eight-week-old C57BL/6 mice, and treated with the most concentrated hUC-PRP sample four days later. Characterization of hUC-PRP and immunotolerance was carried out with multiplex technology, while uterine samples were analyzed by immunohistochemistry and quantitative PCR. The number of embryos and their morphology was determined visually. LARGE SCALE DATA N/A. MAIN RESULTS AND THE ROLE OF CHANCE Platelet density was enhanced three-fold in hUC-PRP compared to that in hUC blood (P < 0.05). hUC-PRP was enriched with growth factors related to tissue regeneration (i.e., hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF-BB), and epidermal growth factor (EGF)), which were released constantly (in vitro) when hUC-PRP was loaded into EndoECM. Both treatments (hUC-PRP alone and hUC-PRP with EndoECM) were immunotolerated and caused significantly regeneration of the damaged endometrium, evidenced by increased endometrial area, neoangiogenesis, cell proliferation and gland density and lower collagen deposition with respect to non-treated uterine horns (P < 0.05). Additionally, we detected augmented gene expression of Akt1, VEGF, and Ang, which are involved in regenerative and proliferation pathways. Finally, hUC-PRP treatment restored pregnancy rates in the mouse model. LIMITATIONS, REASONS FOR CAUTION This proof-of-concept pilot study was based on a murine model of endometrial damage and the use of EndoECM requires further validation prior to clinical implementation for women affected by AS/EA. WIDER IMPLICATIONS OF THE FINDINGS The local administration of hUC-PRP has high impact and is immunotolerated in a murine model of AS/EA, as has been reported in other tissues, making it a promising candidate for heterologous treatment of these endometrial pathologies. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Ministerio de Ciencia, Innovación y Universidades; Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana; and Instituto de Salud Carlos III. The authors do not have any conflicts of interest to declare.

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Section: Discussionsupporting

confidence: 67%

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

Rodríguez-Eguren¹,

Miguel-Gómez²,

Francés-Herrero

et al. 2022

Human Reproduction Open

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“…The release of platelet-derived growth factors, vascular endothelial growth factors, transforming growth factors, and epidermal growth factors from activated platelets results in angiogenesis, cell proliferation, differentiation, and modification of the local immune response ( 238 – 241 ). It can also promote the expression of tissue remodeling genes and reduce fibrosis in mice with Asherman’s syndrome ( 242 ). It has been reported that PRP can improve clinical pregnancy rates and endometrium thickness in patients with RIF ( 231 ).…”

Section: Discussionmentioning

confidence: 99%

Recurrent implantation failure: A comprehensive summary from etiology to treatment

Gao

2023

Front. Endocrinol.

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Implantation is the first step in human reproduction. Successful implantation depends on the crosstalk between embryo and endometrium. Recurrent implantation failure (RIF) is a clinical phenomenon characterized by a lack of implantation after the transfer of several embryos and disturbs approximately 10% couples undergoing in vitro fertilization and embryo transfer. Despite increasing literature on RIF, there is still no widely accepted definition or standard protocol for the diagnosis and treatment of RIF. Progress in predicting and preventing RIF has been hampered by a lack of widely accepted definitions. Most couples with RIF can become pregnant after clinical intervention. The prognosis for couples with RIF is related to maternal age. RIF can be caused by immunology, thrombophilias, endometrial receptivity, microbiome, anatomical abnormalities, male factors, and embryo aneuploidy. It is important to determine the most possible etiologies, and individualized treatment aimed at the primary cause seems to be an effective method for increasing the implantation rate. Couples with RIF require psychological support and appropriate clinical intervention. Further studies are required to evaluate diagnostic method and he effectiveness of each therapy, and guide clinical treatment.

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“…Platelet-rich plasma has also been studied for regeneration of the endometrium in animal models. [95][96][97] Finally, platelet-derived exosomes may play a regenerating role in the endometrium. A recent report suggests cell proliferation and wound healing in in vitro human endometrial cell lines when exposed to platelet-derived exsosomes.…”

Section: Endometrial Regeneration and Use Of Innovative Therapeuticsmentioning

confidence: 99%

Etiology, Risk Factors, and Management of Asherman Syndrome

Khan

2023

Obstetrics &Amp; Gynecology

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Asherman syndrome is characterized by a triad of symptoms including pain, menstrual abnormalities, and infertility and is a result of intrauterine scar tissue after instrumentation of a gravid uterus. Saline sonohysterogram is typically the most sensitive diagnostic tool; however, hysteroscopy is the criterion standard for diagnosis. Treatment includes hysteroscopic-guided lysis of adhesion, with restoration of the anatomy of the uterine cavity. Several modalities are used in an attempt to reduce the reformation of scar tissue after surgery; however, there is no consensus on the ideal method. Stem cells and platelet-rich plasma are being explored as means of regenerative therapy for the endometrium, but data remain limited. At present, most individuals can have restoration of menstrual function; however, lower pregnancy rates and obstetric complications are not uncommon. These complications are worse for patients with a higher grade of disease. Efforts are needed in standardizing classification, reducing uterine instrumentation of the gravid uterus, and referring patients to health care professionals with clinical expertise in this area.

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Human Platelet-Rich Plasma Facilitates Angiogenesis to Restore Impaired Uterine Environments with Asherman’s Syndrome for Embryo Implantation and Following Pregnancy in Mice

Cited by 16 publications

References 65 publications

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

Human umbilical cord platelet-rich plasma to treat endometrial pathologies: methodology, composition and pre-clinical models

Recurrent implantation failure: A comprehensive summary from etiology to treatment

Etiology, Risk Factors, and Management of Asherman Syndrome

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