Regulatory genes involved in the differentiation of mesenchymal stem and progenitor cells

Mesenchymal Stem Cells (MSCs) are clonogenic cells that can grow ex vivo and differentiate in vivo and in vitro into multiple mesodermal phenotypes. They can be isolated from most fetal and adult tissues, including bone marrow, fat, teeth. Moreover, they can easily be expanded and differentiated in vitro. In recent years MSCs have raised great interest for their properties and characteristic as potential therapeutical tools for a wide spectrum of human pathologies. However, several aspects of their biology still need to be clarified. Developmental regulators coding for growth factors, receptors and transcription factors are involved in the regulation of stem and progenitor cells of different tissues. In this view, the present study has been mainly focused on homeodomain transcription factors of different families (Hox, Tale, and Otx) and on the receptor of the Stem Cell Factor (Kit), investigating their possible role in the control of mesenchymal stem and progenitor cells. Different experimental strategies have been employed, including both expression and functional studies in mouse models and human cells. A relevant question is whether MSCs derived from different sources exhibit equivalent biological properties. Here I have compared cellular and molecular characteristics of human MSCs derived from different body locations. Results have highlighted that they exhibit the same immunophenotipic profile, but distinct in vitro growth and differentiation properties, and are characterized by specific HOX codes and TALE signatures. Thus, they may not provide equivalent cell sources for regenerative medicine and tissue engineering. The second issue addressed in my study is whether and how another homebox gene, Otx1, may contribute to the regulation of MSCs. Otx1 encodes a key factor in neural development and plays an important role also in blood cell production. Here I showed that Otx1 expression is modulated during the osteogenic differentiation of both murine and human MSCs and its inactivation is associated with phenotypical alterations and enhanced survival and proliferation of MSCs, as well as an impairment of their osteogenic capacity. These findings indicate that Otx1 is implicated in the control of both proliferation and differentiation of MSCs. Finally, another important pleiotropic molecule is Kit, coding for the Stem Cell Factor (SCF) tyrosine-kinase receptor. Kit is a pivotal regulator of several types of stem and progenitor cells. However, its role in MSCs is still controversial. My results have shown that Kit is active also in MSCs, providing the first evidence on its involvement in the adipogenic process. The identification of new molecular cues controlling self-renewal, commitment and differentiation of mesenchymal stem and progenitor cells has both biological and clinical relevance.