PIOMES · Pbx proteins as pioneer factors promoting signal specificity in mesodermal differentiation

Pbx proteins as pioneer factors promoting signal specificity in mesodermal differentiation

The mesoderm is one of the three primary germ layers in the early embryo and gives rise to a large variety of tissues, including muscle, bone, blood, cartilage and connective tissues. Understanding how mesodermal tissues develop from progenitor cells is critical to develop efficient protocols applicable to tissue repair and regenerative therapies. In mammals, all mesodermal progenitors (MPs) originate during gastrulation from cells of the epiblast that ingress into a transient structure termed primitive streak (PS). In the PS, the coordinated action of different signalling pathways (Nodal, Wnt, Bmp) and transcription factors (TFs) provides the spatio-temporal information specifying distinct mesodermal cell types. However, how MPs acquire mesodermal fate is still an open question, due to the complexity of deciphering the transcriptional networks at gastrulation (Figure 1). In PIOMES we found that genes conferring positional identity, like the Pbx proteins, are important for attributing such spatio-temporal coordinates. Pbx TFs have widespread roles in the formation of lateral mesoderm-derived structures, such as blood, appendicular skeleton, heart, spleen, and body wall. Pbx mutants die at embryonic day (E) 8.5 displaying dilated heart, defective somite formation, short trunk, turned tail and limbs aplasia. In PIOMES we found that Pbx1 is initially expressed in epiblast cells preceding gastrulation, and becomes upregulated in the posterior PS and emerging mesodermal cells at E6.5 and E7.5. Consistently, we observed that while the anterior PS and the node of E7.5 Pbx mutant embryos were unaffected, the posterior PS was shorter and abnormally shaped. All above observations raised the possibility that Pbx proteins guide mesoderm specification of the posterior MPs through specific transcriptional networks. In PIOMES we employed mouse epiblast stem cells (mEpiSCs), which can be differentiated in vitro into different MPs subtypes and thus are an excellent system for understanding how complex transcriptional regulatory networks control lineage determination. mEpiSCs share a common pluripotent state with the human embryonic stem cells (hESCs), and thus represent the closer model for translating the mouse results into the hESCs system. In PIOMES we had implemented protocol for mesoderm differentiation. Loss of MPs underlies a spectrum of developmental and degenerative diseases, such as congenital heart defects, muscular dystrophies. In PIOMES we identified critical molecular mechanisms driving mesoderm specification that will help to conceive new protocols for human stem-cell therapy and open new avenues for regenerative medicine.

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