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. 2017 May;35(5):1365-1377.
doi: 10.1002/stem.2574. Epub 2017 Mar 1.

Murine Rankl-/- Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector

Francesca Schena  1 , Ciro Menale  2   3 , Emanuela Caci  4 , Lorenzo Diomede  2   3 , Eleonora Palagano  3   5 , Camilla Recordati  6 , Monica Sandri  7 , Anna Tampieri  7 , Ileana Bortolomai  2   8 , Valentina Capo  8 , Claudia Pastorino  1 , Arinna Bertoni  1   9 , Marco Gattorno  1 , Alberto Martini  1 , Anna Villa  2   3 , Elisabetta Traggiai  1   10 , Cristina Sobacchi  2   3
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Murine Rankl-/- Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector

Francesca Schena et al. Stem Cells. 2017 May.

Abstract

Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl-/- mice, and found that Rankl-/- BM-MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl-/- BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics. Stem Cells 2017;35:1365-1377.

Keywords: Bone; Differentiation; Lentiviral transduction; Mesenchymal stromal cell; Osteopetrosis; Rankl.

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