TY - JOUR
T1 - Mesenchymal Stromal Cell-Seeded Biomimetic Scaffolds as a Factory of Soluble RANKL in Rankl-Deficient Osteopetrosis
AU - Menale, Ciro
AU - Campodoni, Elisabetta
AU - Palagano, Eleonora
AU - Mantero, Stefano
AU - Erreni, Marco
AU - Inforzato, Antonio
AU - Fontana, Elena
AU - Schena, Francesca
AU - van't Hof, Rob
AU - Sandri, Monica
AU - Tampieri, Anna
AU - Villa, Anna
AU - Sobacchi, Cristina
N1 - Funding Information:
We thank Dario Strina and Sonia Valentino for technical support. This work was partially supported by the European Community's Seventh Framework Program (FP7/2007-2013, SYBIL Project) and PRIN Project (2015F3JHMB_004) to AV, and by Programma Nazionale per la Ricerca-Consiglio Nazionale delle Ricerche Aging Project to AV. AI is recipient of a Young Investigator Grant from Ministero della Salute (GR-2011-02349539). CM is recipient of a fellowship founded by Fondazione Nicola Del Roscio.
Publisher Copyright:
© 2018 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
PY - 2019/1
Y1 - 2019/1
N2 - Biomimetic scaffolds are extremely versatile in terms of chemical composition and physical properties, which can be defined to accomplish specific applications. One property that can be added is the production/release of bioactive soluble factors, either directly from the biomaterial, or from cells embedded within the biomaterial. We reasoned that pursuing this strategy would be appropriate to setup a cell-based therapy for RANKL-deficient autosomal recessive osteopetrosis, a very rare skeletal genetic disease in which lack of the essential osteoclastogenic factor RANKL impedes osteoclast formation. The exogenously administered RANKL cytokine is effective in achieving osteoclast formation and function in vitro and in vivo, thus, we produced murine Rankl −/− mesenchymal stromal cells (MSCs) overexpressing human soluble RANKL (hsRL) following lentiviral transduction (LVhsRL). Here, we described a three-dimensional (3D) culture system based on a magnesium-doped hydroxyapatite/collagen I (MgHA/Col) biocompatible scaffold closely reproducing bone physicochemical properties. MgHA/Col-seeded murine MSCs showed improved properties, as compared to two-dimensional (2D) culture, in terms of proliferation and hsRL production, with respect to LVhsRL-transduced cells. When implanted subcutaneously in Rankl −/− mice, these cell constructs were well tolerated, colonized by host cells, and intensely vascularized. Of note, in the bone of Rankl −/− mice that carried scaffolds with either WT or LVhsRL-transduced Rankl −/− MSCs, we specifically observed formation of TRAP + cells, likely due to sRL released from the scaffolds into circulation. Thus, our strategy proved to have the potential to elicit an effect on the bone; further work is required to maximize these benefits and achieve improvements of the skeletal pathology in the treated Rankl −/− mice. Stem Cells Translational Medicine 2019;8:22–34.
AB - Biomimetic scaffolds are extremely versatile in terms of chemical composition and physical properties, which can be defined to accomplish specific applications. One property that can be added is the production/release of bioactive soluble factors, either directly from the biomaterial, or from cells embedded within the biomaterial. We reasoned that pursuing this strategy would be appropriate to setup a cell-based therapy for RANKL-deficient autosomal recessive osteopetrosis, a very rare skeletal genetic disease in which lack of the essential osteoclastogenic factor RANKL impedes osteoclast formation. The exogenously administered RANKL cytokine is effective in achieving osteoclast formation and function in vitro and in vivo, thus, we produced murine Rankl −/− mesenchymal stromal cells (MSCs) overexpressing human soluble RANKL (hsRL) following lentiviral transduction (LVhsRL). Here, we described a three-dimensional (3D) culture system based on a magnesium-doped hydroxyapatite/collagen I (MgHA/Col) biocompatible scaffold closely reproducing bone physicochemical properties. MgHA/Col-seeded murine MSCs showed improved properties, as compared to two-dimensional (2D) culture, in terms of proliferation and hsRL production, with respect to LVhsRL-transduced cells. When implanted subcutaneously in Rankl −/− mice, these cell constructs were well tolerated, colonized by host cells, and intensely vascularized. Of note, in the bone of Rankl −/− mice that carried scaffolds with either WT or LVhsRL-transduced Rankl −/− MSCs, we specifically observed formation of TRAP + cells, likely due to sRL released from the scaffolds into circulation. Thus, our strategy proved to have the potential to elicit an effect on the bone; further work is required to maximize these benefits and achieve improvements of the skeletal pathology in the treated Rankl −/− mice. Stem Cells Translational Medicine 2019;8:22–34.
KW - Biomimetic scaffold
KW - Cell therapy
KW - Gene therapy
KW - Mesenchymal stromal cell
KW - Osteopetrosis
KW - RANKL
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U2 - 10.1002/sctm.18-0085
DO - 10.1002/sctm.18-0085
M3 - Article
C2 - 30184340
AN - SCOPUS:85053272764
SN - 2157-6564
VL - 8
SP - 22
EP - 34
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 1
ER -