Vol.:(0123456789) 1 3 https://doi.org/10.1007/s12015-017-9794-5 Bone Marrow Mesenchymal Stem Cells Carrying FANCD2 Mutation Difer from the Other Fanconi Anemia Complementation Groups in Terms of TGF-β1 Production Ilgin Cagnan 1  · Aysen Gunel‑Ozcan 1  · Fatima Aerts‑Kaya 1  · Najim Ameziane 2  · Baris Kuskonmaz 3  · Josephine Dorsman 2  · Fatma Gumruk 4  · Duygu Uckan 1,3 © Springer Science+Business Media, LLC, part of Springer Nature 2017 Abstract Transforming growth factor beta (TGF-β) secretion from cells in the bone marrow (BM) niche afects hematopoietic stem cell (HSC) fate and has a cardinal role in HSC quiescence. BM mesenchymal stem cells (BM-MSCs), a component of the BM niche, may produce abnormal levels of TGF-β in Fanconi anemia (FA) and may play a role in bone marrow failure. Here, we molecularly and cellularly characterized FA BM-MSCs by addressing their immunophenotype, proliferation- and diferentiation- capacity, reactive oxygen species (ROS) production, senescence activity as well as expression and secretion levels of TGF-β isoforms. In ten FA patients, mutations were detected in FANCA (n = 7), FANCG (n = 1) and FANCD2 (n = 2) genes. The immunophenotype, with the exception of CD29, and diferentiation capacity of FA BM-MSCs were similar to healthy donors. FA BM-MSCs showed decreased proliferation, increased ROS level and an arrest in G2 following DEB treat- ment. β-galactosidase staining indicated elevated senescence of FANCD2-defcient cells. FA BM-MSCs displayed TGF-β1 mRNA levels similar to donor BM-MSCs, and was not afected by DEB treatment. However, secretion of TGF-β was absent in FA-D2 BM-MSCs. Absence of TGF-β secretion may be related to early onset of senescence of the FANCD2-defcient BM-MSCs. The proliferative response of FA-D2 BM-MSCs to rTGF-β1 was not diferent from FANCA-defcient and donor cells and raises the possibility that rTGF-β1 may reverse the senescence of the FANCD2-defcient BM-MSCs which needs to be investigated further. Keywords TGF-BETA · Bone marrow · Mesenchymal stem cells · Fanconi anemia · FANCD2 Introduction Hematopoietic stem cell (HSC) and progenitor numbers are in a delicate balance, regulated by complex signaling [ 1]. In the bone marrow (BM), homeostasis of hemat- opoietic cells is orchestrated by intrinsic signaling path- ways, as well as crosstalk between the HSCs and its niche components, such as BM stroma [2]. Multipotent mesen- chymal stem cells (MSCs) are important components of the BM stroma [3], and may affect the balance between HSC self-renewal and differentiation. Impairment of the crosstalk between HSC and the BM stromal cells can lead progressive bone marrow failure (BMF) and hematopoi- etic malignancies [4]. Accumulation of DNA damage causes hematopoietic aging throughout life and is accelerated in DNA repair deficiencies, such as Fanconi anemia (FA) [5, 6]. FA (MIM 227,650) is a hereditary disease, which is classifed Electronic Supplementary Material The online version of this article (https://doi.org/10.1007/s12015-017-9794-5) contains supplementary material, which is available to authorized users. * Aysen Gunel-Ozcan agozcan@hacettepe.edu.tr 1 Department of Stem Cell Sciences, Institute of Health Sciences, Center for Stem Cell Research and Development, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey 2 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Pediatrics, Division of Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey 4 Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Ankara, Turkey Stem Cell Reviews and Reports (2018) 14: – 3 425 4 7 Published online: 1 201 December 7 5