Abstract
The culture of progenitor mesenchymal stem cells (MSC) onto osteoconductive materials to induce a proper osteogenic differentiation and mineralized matrix regeneration represents a promising and widely diffused experimental approach for tissue-engineering (TE) applications in orthopaedics. Among modern biomaterials, calcium phosphates represent the best bone substitutes, due to their chemical features emulating the mineral phase of bone tissue. Although many studies on stem cells differentiation mechanisms have been performed involving calcium-based scaffolds, results often focus on highlighting production of in vitro bone matrix markers and in vivo tissue ingrowth, while information related to the biomolecular mechanisms involved in the early cellular calcium-mediated differentiation is not well elucidated yet. Genetic programs for osteogenesis have been just partially deciphered, and the description of the different molecules and pathways operative in these differentiations is far from complete, as well as the activity of calcium in this process. The present work aims to shed light on the involvement of extracellular calcium in MSC differentiation: a better understanding of the early stage osteogenic differentiation program of MSC seeded on calcium-based biomaterials is required in order to develop optimal strategies to promote osteogenesis through the use of new generation osteoconductive scaffolds. A wide spectrum of analysis has been performed on time-dependent series: gene expression profiles are obtained from samples (MSC seeded on calcium-based scaffolds), together with related microRNAs expression and in vivo functional validation. On this basis, and relying on literature knowledge, hypotheses are made on the biomolecular players activated by the biomaterial calcium-phosphate component. Interestingly, a key role of miR-138 was highlighted, whose inhibition markedly increases osteogenic differentiation in vitro and enhance ectopic bone formation in vivo. Moreover, there is evidence that Ca-P substrate triggers osteogenic differentiation through genes (SMAD and RAS family) that are typically regulated during dexamethasone (DEX) induced differentiation.
Highlights
Among all stem cells reservoirs, bone marrow still remain the most commonly used worldwide, since it represents a reservoir of multi-potent mesenchymal stem cells (MSC) able to differentiate in vitro toward several lineages [3], offering high potential for their use in regenerative medicine applications
In order to overcome the very low frequency of occurrence among bone marrow nucleated cells, bone marrow derived MSC are typically expanded in monolayer (2D), due to their capacity to adhere to a plastic surface, before their use in combination with three-dimensional (3D) porous scaffolds
4,03 3,02 5,60 3,40 identification of signalling cascades that are triggered in progenitor cells by calcium phosphate (CaP) based scaffolds is an essential step in understanding the mechanism of cellular activation/differentiation that culminates in bone formation in vivo
Summary
In the last two decades, the knowledge advancement in the fields of stem cell have highlighted the possibility to harvest and manipulate in vitro adult mesenchymal stem cells derived from various tissues, including bone marrow, periostium, skeletal muscle, adipose tissue, skin and retina [1,2,3,4,5,6,7,8,9,10,11,12,13].Among all stem cells reservoirs, bone marrow still remain the most commonly used worldwide, since it represents a reservoir of multi-potent mesenchymal stem cells (MSC) able to differentiate in vitro toward several lineages [3], offering high potential for their use in regenerative medicine applications. MSC combined with porous bioceramics have been used with excellent results to repair large bone defects in both animal and human pilot clinical studies [17, 19, 23]. These results have opened new frontiers addressed to the investigation of biological and molecular mechanisms of MSC differentiation, and on the influence of the artificial microenvironment affecting the cellular activity [24]. When implanted in ectopic model, MSC are able to reconstitute an organoid composed of both MSC derived bone tissue and bone marrow tissue originated from host hematopoietic progenitors [30]
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