Introduction: Fanconi anemia (FA) is an inherited disorder characterized by
bone marrow failure, congenital malformations, and predisposition to malignancies.
Alterations in hematopoietic stem cells (HSC) have been reported, but little is known
regarding the bone marrow (BM) stroma. Thus, the characterization of Mesenchymal
Stromal Cells (MSC) would help to elucidate their involvement in the BM failure.
Methods: We characterized MSCs of 28 FA patients (FA-MSC) before and after
treatment (hematopoietic stem cell transplantation, HSCT; or gene therapy, GT).
Phenotypic and functional properties were analyzed and compared with MSCs
expanded from 26 healthy donors (HD-MSCs). FA-MSCs were genetically
characterized through, mitomycin C-test and chimerism analysis. Furthermore, RNA-
seq profiling was used to identify dysregulated metabolic pathways. Results: Overall,
FA-MSC had the same phenotypic and functional characteristics as HD-MSC. Of note,
MSC-GT had a lower clonogenic efficiency and MSC- HSCT had a lower ability to
inhibit mitogen-induced T-cell proliferation. These findings were not confirmed in the
whole FA patients cohort. Transcriptomic profiling identified dysregulation in HSC
self-maintenance pathways in FA-MSC (HOX), confirmed by real-time quantitative
polymerase chain reaction (RT-qPCR). Discussion: Our study provides a
comprehensive characterization of FA-MSCs, including for the first time MSC-GT and
constituting the largest series published to date. Interestingly, transcript profiling
revealed dysregulation of metabolic pathways related to HSC self-maintenance. Taken
together, our results or findings provide new insights into the pathophysiology of the
disease, although whether these niche defects are involved in the hematopoietic defects
seen of FA deserves further investigation. Less...