hUC-MSCs loaded collagen scaffold for refractory thin endometrium caused by Asherman syndrome: a double-blind randomized controlled trial

Abstract

In this single-center, double-blinded, randomized controlled trial, we investigated whether human umbilical cord-derived mesenchymal stromal cells loaded collagen scaffolds (hUC-MSC/CS) could improve the cumulative live-birth rate (cLBR) in infertile women with refractory thin endometrium (RTE). We randomly assigned 25 subfertile women with RTE, in a 1:1 ratio, to receive hysteroscopic adhesiolysis and plowing plus either hUC-MSC/CS or saline/CS (control) for intrauterine implantation. Uterine fluid was collected on the embryo transfer day for RNA-sequencing to explore the potential mechanisms by which hUC-MSCs exert their effects. The primary outcome was the cLBR. Live births occurred in 3 out of 11 women in the hUC-MSC/CS group and in 1 out of 13 women in the control group (27.3% vs 7.7%; relative risk [RR], 3.55; 95% confidence interval [CI], 0.43 to 29.42; P = .30). The cumulative frequencies of clinical pregnancy were 5/11 and 1/13 in the hUC-MSC/CS group and control group, respectively (45.5% vs. 7.7%; RR, 5.91; 95% CI, 0.81-43.28; P = .06). Two of 11 participants developed urticaria in the hUC-MSC/CS group. Enrichment analysis showed that T-cell activation had the largest proportion in the biological process category. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that most genes were related to cytokine-cytokine receptor interaction. In conclusion, there was a non-significant trend toward a higher cLBR with hUC-MSC/CS compared to controls, potentially through the cytokine-cytokine receptor interaction pathway. hUC-MSCs appeared to be relatively safe in a 1-year follow-up. Therefore, this novel therapy can be proposed to patients with RTE.

Keywords: Asherman syndrome; clinical trial; intrauterine adhesion; mesenchymal stem cell; thin endometrium.

Graphical Abstract

Figure 1.

CONSORT flow diagram.

Figure 2.

Identification and enrichment analysis of RNA-Seq differentially expressed genes (DEGs) and cell proportion analysis between hUC-MSC/CS participants and controls. Volcano plot (A) and heatmap (B) showing 41 up- and 3 downregulated DEGs (adjusted P-value < .05 and log₂FC > 1) in uterine fluid samples from hUC-MSC/CS participants (n = 5) and controls (n = 6). (C) PCA scores plot to show 2 well-defined groups. Gene Ontology analysis in the biological process (D), cellular component (E), and molecular function terms (F) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis (G) for all 44 DEGs in the hUC-MSC/CS group. (H) The gene-pathway network was structured to identify key target genes. The proportion of endometrial cells (I) and immune cells (J) between hUC-MSC/CS participants and controls.