Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

• Published in: Stem cell research & therapy Vol. 8; no. 1; p. 265
• Main Authors: Aquino-Martínez, Rubén, Angelo, Alcira P, Pujol, Francesc Ventura
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16-11-2017; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Bone biomaterials; Bone grafts; Bone growth; Bone marrow; Bone morphogenetic protein; Bone morphogenetic protein 2; Bone morphogenetic proteins; Bone remodeling; Bone surgery; Bones; Bones growth; Calci; Calcium; Calcium sequestration; Calcium sulfate; Cell adhesion & migration; Cell culture; Cell differentiation; Cell migration; Computed tomography; Creixement dels ossos; Cytokines; Cèl·lules mare; Gene expression; Growth factors; Health aspects; Kinases; Mesenchymal stem cells; Mesenchyme; Migració cel·lular; Migration; Molecular modelling; Ossos; Osteoblasts; Osteogenesis; Osteoinduction; Parietal bone; Physiology; Progenitor cells; Regeneration; Skin & tissue grafts; Stem cells; Transplants & implants; Wortmannin; Wound healing; Bone grafts; Bone morphogenetic protein; Bone regeneration; Migration; Osteoinduction; Craniofacial; Bone remodeling; Calcium sulfate; Mesenchymal stem cells
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-017-0713-0

Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC) recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca
-containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO
) on MSC migration. In addition, to evaluate the influence of CaSO
on MSC differentiation and the potential molecular mechanisms involved.
A circular calvarial bone defect (5 mm diameter) was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO
concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO
effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO
treatment was also evaluated by qPCR.
CaSO
increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO
significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO
-containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO
and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO
effects on MSC migration.
Specific CaSO
concentrations induce bone regeneration of calvarial defects in part by acting on the host's undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO
regulates BMP-2-induced MSC migration by differentially activating the PI3K/AKT pathway. Altogether, these results suggest that CaSO
scaffolds could have potential applications for bone regeneration.