Making More Womb: Clinical Perspectives Supporting the Development and Utilization of Mesenchymal Stem Cell Therapy for Endometrial Regeneration and Infertility

Abstract

The uterus is a homeostatic organ, unwavering in the setting of monthly endometrial turnover, placental invasion, and parturition. In response to ovarian steroid hormones, the endometrium autologously prepares for embryo implantation and in its absence will shed and regenerate. Dysfunctional endometrial repair and regeneration may present clinically with infertility and abnormal menses. Asherman’s syndrome is characterized by intrauterine adhesions and atrophic endometrium, which often impacts fertility. Clinical management of infertility associated with abnormal endometrium represents a significant challenge. Endometrial mesenchymal stem cells (MSC) occupy a perivascular niche and contain regenerative and immunomodulatory properties. Given these characteristics, mesenchymal stem cells of endometrial and non-endometrial origin (bone marrow, adipose, placental) have been investigated for therapeutic purposes. Local administration of human MSC in animal models of endometrial injury reduces collagen deposition, improves angiogenesis, decreases inflammation, and improves fertility. Small clinical studies of autologous MSC administration in infertile women with Asherman’s Syndrome suggested their potential to restore endometrial function as evidenced by increased endometrial thickness, decreased adhesions, and fertility. The objective of this review is to highlight translational and clinical studies investigating the use of MSC for endometrial dysfunction and infertility and to summarize the current state of the art in this promising area.

The Role of Endometrial Stem/Progenitor Cells in Recurrent Reproductive Failure

“…Non-resident endometrial SPCs (including BMDMSCs) and non-endometrial MSCs (such as umbilical cord-derived, amniotic-derived, or adipose-derived MSCs) are other additional stem cell populations that have been previously explored in relation to endometrial regeneration [ 62 ], and lie beyond the scope of this review. Only those SPCs derived from the endometrial cell types (e.g., epithelial and stromal) will be included in this review with regards to the aetiology of RRF.…”

“…Therefore, studies are urgently required to explore the fundamental role of eSPCs in the pathogenesis of RIF and RPL, as well as to assess their therapeutic potential in the management of these conditions. Furthermore, common and challenging clinical conditions that are related to RRF include thin endometrium and AS, for which studies have been undertaken to aid clinical management with the use of eSPCs [ 62 , 126 ].…”

“…It is possible that RRF may also arise from an abnormal glandular network, secondary to aberrant eSPCs. Dysfunctional endometrial repair may present in women with infertility, RIF, or RPL, and may be implicated in the aetiology of clinical conditions such as Asherman’s syndrome (AS) and a persistently thin endometrium [ 62 ]. AS is a condition whereby intrauterine adhesions result in a thin or defective endometrium, due to probable extensive destruction of the basalis glands (usually protected from external influence), thereby impacting the functionalis, and consequentially embryo implantation and pregnancy [ 48 , 63 ].…”

“…Evidence is emerging that RPL is associated with a depletion of highly proliferative mesenchymal cells that act as decidual precursors and are likely to originate from bone marrow-derived mesenchymal stem/stromal cells (BMDMSCs) [ 64 ]. The use of exogenous, autologous, or allogenic stem cells has been proposed in regenerative medicine, including the treatment of atrophic or scarred endometrium [ 62 , 65 ]. These have shown promise for the clinical application of SPC therapy in endometrium-related gynaecological pathologies and fertility, with reports of BMDMSCs used to improve endometrial thickness and vascularity, restore menses, and aid conception in patients with AS or endometrial atrophy [ 65 , 66 , 67 , 68 , 69 ].…”

“…Although evidence is now emerging on the possible link between non-eSPCs and RRF, little is known about the resident eSPCs and their association with these pathologies [ 62 , 70 ]. Evidently, much work is required in the characterisation and clinical application of eSPCs in such disorders.…”