What happens inside the uterine lining after regenerative cell therapy?
The endometrium, the tissue that lines the uterus, renews itself throughout the menstrual cycle. This process depends on the coordinated activity of epithelial cells, stromal cells, blood vessels and immune cells. Its remarkable regenerative capacity makes it one of the most dynamic tissues in the human body.
In Asherman syndrome, healthy endometrium is partly replaced by fibrotic scar tissue that can form intrauterine adhesions, affecting menstruation, embryo implantation and fertility.
A recent phase 1/2 clinical study led by researchers at the Carlos Simon Foundation examined what happens inside the endometrium after an experimental therapy using autologous CD133+ bone marrow-derived cells. The researchers studied not only changes in endometrial thickness, but also tissue structure, cell populations and gene activity before and after treatment.
Regeneration is more than increasing endometrial thickness
Endometrial thickness is commonly assessed during fertility treatment, but it provides only one measure of tissue condition. A functional endometrium also needs glands, blood vessels, supportive stromal tissue and a balanced cell-cell communication cross talk.
The study included 20 women with moderate or severe Asherman syndrome who had not responded to previous hysteroscopic treatments. After cell therapy, the researchers observed increases in endometrial thickness and volume, together with improvements in the reduction of intrauterine adhesions within the uterine cavity. Histological analysis also showed a 62% increase in the proportion of glands, a 64% reduction in fiber-rich stromal tissue and a 73% increase in blood vessels within the stroma, highlighting a morphological improvement in the treated endometrium.
What changed inside the endometrium?
Asherman syndrome creates a tissue environment characterized by fibrosis, inflammation and impaired vascular development. To understand whether the therapy altered this environment, the researchers analyzed more than 123,000 individual cells from endometrial biopsies collected before and after treatment and analysed it by single cell RNA sequencing.
After therapy, they detected a reduction in a disease-associated epithelial population and in macrophages, immune cells that can contribute to persistent inflammation. They also observed changes in epithelial, stromal, endothelial and perivascular cells, which support the structure and function of the endometrium.
Gene activity associated with tissue remodeling, secretory function, regeneration and blood vessel formation increased, while several inflammatory signals decreased. Communication between cells involved in repair and vascular regeneration also changed.
Together, these findings suggest that the endometrium shifted toward an environment more compatible with tissue repair and thus closer resembled the healthy tissue.
What happened to the administered cells?
A central question in cell therapy is whether the administered cells become part of the tissue or mainly act by releasing signals that influence surrounding cells.
The researchers explored this question by tracking naturally occurring variations in the mitochondrial DNA of the CD133+ cells. The researchers identified mitochondrial variants in the infused autologous CD133+ cells and then searched for the same variants in endometrial cells collected after treatment. Their appearance only after treatment was interpreted as evidence that infused cells had engrafted and contributed clonally to endometrial repair. Although the analysis was carried out in only three participants, it provides initial insights about the possible mechanism of action.
Organoids offer another view of recovery
The team also generated endometrial organoids from samples collected before and after treatment.
Organoids are three-dimensional structures grown in the laboratory that reproduce some characteristics of the original tissue. They allow researchers to study how endometrial cells grow and organize under controlled conditions.
Organoids derived from post-treatment samples showed a greater initial capacity to form than those generated before therapy. Their cellular composition also moved partially toward the pattern observed in organoids from healthy endometrium.
What do the clinical results show?
The main objective of this phase 1/2 trial was to assess safety and tolerability. No serious adverse events related to the cell product were reported during the 15-month follow-up.
The study also recorded six live births among the 20 participants, with three vaginal deliveries and 3 caesarean sections. One followed a spontaneous pregnancy and five occurred after assisted reproduction. No congenital abnormalities, neonatal infections or significant neonatal adverse events were reported during the first month.
These outcomes are relevant, but they must be interpreted carefully as the study involved a small number of patients. Additionally, reproductive outcomes can also be influenced by embryo quality, transfer timing and disease severity. Larger controlled studies will therefore be needed to determine how effective the therapy is and which patients may benefit most.
A broader view of endometrial regeneration
The study provides a more detailed picture of what endometrial regeneration may involve after stem cell therapy. The findings suggest that repair depends on several processes acting together: reducing fibrosis and inflammation, restoring communication between cells and promoting a more functional tissue environment.
Article reference
Santamaria X, Pardo-Figuerez M, González-Fernández J, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for Asherman Syndrome: a phase 1/2 trial. Nature Communications. 2026;17:1093. https://doi.org/10.1038/s41467-025-67850-x