Perivascular Endometrial Injury Mesenchymal Stem Cells in Recurrent Implantation Failure

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Improvements in reproductive techniques have resulted in the live birth rates from IVF procedures increasing from 5% to approximately 30% in recent decades but have plateaued since. Emerging preclinical and clinical data implicates endometrial receptivity deficiencies in patients with Recurrent Implantation Failure (RIF) as the predominant factor hindering successful implantation. Mechanisms on how Local Endometrial Injury (LEI) improves implantation rates in patients with RIF are currently unknown.

In Vitro Fertilization (IVF) has allowed 30% of couples facing infertility to successfully achieve viable pregnancies. However, there are patients who repeatedly fail to fall pregnant despite transfers of good quality embryos. Recurrent Implantation Failure (RIF) in our hospital setting refers to cases where women failed to achieve a clinical pregnancy after a transfer of four good-quality embryos in a minimum of two IVF cycles. Until recently, one of the most often used adjunct therapies in IVF was to generate a Local Endometrial Injury (LEI) known as endometrial scratching, in an attempt to improve success rates. In fact, eighty-three percent of clinicians from United Kingdom, Australia, and New Zealand recommend LEI in a survey conducted as recently as 2015.

Since the initial case report in 2003, multiple trials of LEI have been conducted which generally only showed benefit in those with RIF, but not in other unselected populations. The lack of high quality Randomized Controlled Trials (RCTs), the different definitions of RIF and the varied types of intervention led to the use of meta-analyses to guide clinical practice. More recently, high quality RCTs have shown opposing findings, albeit with different patient groups and LEI intervention protocols.

The proposed mechanism of action with LEI ranges from mechanical disruption to the endometrium correcting the asynchrony between endometrial and embryo stages, with a wound healing response possibly influencing immune cell perturbations and activation states favoring implantation and enhanced decidualization. Another theory is that LEI induces an inflammatory reaction involving cytokines, macrophages and other immune cells. However, none adequately explain how LEI in a cycle prior to embryo transfer promotes implantation leading to pregnancy and live birth. This study demonstrates that endometrial injury activates endometrial stem/progenitor cells in the basal layer to proliferate and provide replacement cells, resulting in the production of a more cellular and thicker functional layer in the subsequent cycle, a concept that can explain carryover effect of LEI in improving endometrial receptivity in the subsequent cycle, given that the basal layer remains during menstruation.

Endometrial stem/progenitor cells were first reported as clonogenic epithelial and stromal cells, which could self-renew in vitro by serial cloning, had high proliferative activity and differentiated into large gland-like structures in 3D culture and mesodermal lineages, respectively. SUSD2 + cells comprised 4.2% of the freshly sorted endometrial stromal cells which differentiated into adipocytes, osteocytes, chondrocytes, myocytes, and endothelial cells, and generated endometrial stromal-like tissue in vivo. These eMSCs are also reduced in obese women with a history of reproductive failure, indicative of a role they play in fertility.

Therefore, we aimed to investigate the impact of LEI on eMSCs and determine if LEI alters their proportion and capacity for decidualization, which in turn affects endometrial tissue remodeling explaining the improved rates of pregnancy outcomes post LEI and we sought to determine perturbations in the perivascular eMSC compartment after a luteal phase LEI in women with RIF.

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Rose Alpine
editor.jcms@jpeerreview.com