Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia

Mantelli, Melissa; Avanzini, Maria Antonietta; Rosti, Vittorio; Ingo, Daniela; Conforti, Antonella; Novara, Francesca; Arrigo, Giulia; Boni, Marina; Zappatore, Rita; Lenta, Elisa; Moretta, Antonia; Acquafredda, Gloria; Silvestri, Annalisa De; Cirillo, Valentina; Cicchetti, Elisa; Algeri, Mattia; Strocchio, Luisa; Vinti, Luciana; Starc, Nadia; Biagini, Simone; Sirleto, Pietro; Bernasconi, Paolo; Zuffardi, Orsetta; Maserati, Emanuela; Maccario, Rita; Zecca, Marco; Locatelli, Franco; Bernardo, Maria Ester

doi:10.1111/bjh.13504

Cited by 24 publications

(28 citation statements)

References 29 publications

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“…1B). These results are in line with the previous studies that show that FA MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages [20].…”

Section: Discussionsupporting

confidence: 93%

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Cole

et al. 2018

Stem Cells

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Hematopoietic stem cells preserve their ability to self-renew and differentiate to different lineages in the bone marrow (BM) niche, which is composed in large part by BM stromal cells. Studies have shown that altered signaling in the BM niche results in leukemia initiation or progression. Fanconi anemia (FA) is an inherited BM failure syndrome associated with extremely high risk of leukemic transformation. By using two FA mouse models, here we have investigated the hematopoiesis-supportive function of FA BM mesenchymal stroma cells (MSCs). We found that MSCs deficient for Fanca or Fancc gene are defective in proliferation and prone to undergo senescence in vitro. Mechanistically, we show that the activity of cell division control protein 42 (Cdc42), a Rho GTPase known to be a critical regulator for cytoskeleton organization, is significantly reduced in FA MSCs. Furthermore, we demonstrate that this reduction in Cdc42 activity plays a causal role in defective hematopoiesis-supportive function of the FA MSCs. The progenies of wild-type hematopoietic stem and progenitor cells cocultured on FA MSCs exhibit compromised self-renewal capacity both in vitro and in vivo. Genetic correction of FA deficiency restores Cdc42 activity and improves the hematopoiesis-supportive capacity of FA MSC. Finally, ectopic expression of a constitutively active Cdc42 mutant, Cdc42F28L, or pretreatment with Wnt5a, increases the active Cdc42 level and rescues the hematopoietic supportive defects of FA MSCs. Taken together, our results identify a novel link between Cdc42 activity and the hematopoiesis-supportive function of MSCs and suggest that a niche-specific increase of Cdc42 activity may be beneficial for FA therapy. Stem Cells 2018;36:785-795.

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“…1B). These results are in line with the previous studies that show that FA MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages [20].…”

Section: Discussionsupporting

confidence: 93%

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Cole

et al. 2018

Stem Cells

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“…BM MSC are responsible for bone tissue development and maintenance, and they also give rise to other supporting cell types, including adipocytes and chondrocytes. In FA, only a few studies looked at BM MSC function (using different models and approaches) and showed inconsistent and contradictory results . Some of these studies agreed that FA‐derived BM MSC exhibit cellular deficits, including increased senescence and reduced proliferation, whereas others only found subtle changes in their ability to support hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

Mazon¹,

Julien²,

Ung³

et al. 2018

Journal of Bone and Mineral Research

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Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial-ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA and FancC embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC mice show reduced bone strength compared with their wild-type littermates. Ex vivo cultures showed that FancA and FancC bone marrow-derived mesenchymal stem cells ( MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. © 2018 American Society for Bone and Mineral Research.

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“…48 Several previous studies indicated that MSPC from FA patients display reduced long-term proliferation ability and spontaneous chromosome breakages. 49–51 In addition, we have previously reported that MSPC from the murine Fancg − / − model exhibit impaired proliferative capacity. 30 Amarachintha et al .…”

Section: Discussionmentioning

confidence: 99%

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia

Zhou

Xing

et al. 2017

Haematologica

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Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.

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Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia

Cited by 24 publications

References 29 publications

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia

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