Our group has defined a minoritarian cardiac subpopulation B-CPC (see figure 1), characterized by the expression of the transcriptional factor Bmi1, enriched in cardiac stem cells (CSC) and cardiac progenitor cells (CPC). B-CPC is a heterogeneous population that can become any of the three main cardiac cell lineages, both in homeostasis and after acute injury. B-CPC are localized in perivascular locations, mainly in some cardiac specialized endothelial domains (low-oxidative stress structures). This low oxidative environment reduces B-CPC mitophagy and slow metabolism, protecting B-CPC from the generalized age-related oxidative stress. This represents in adult heart the endothelial niche, as in other adult stem cell compartments and the intime interaction with endothelium keeps B-CPC in a quiescent status. As previously established in skeletal muscle, we have confirmed a bidirectional regulation; B-CPC secrete high levels of the chemokine CXCL12 to maintain endothelium in their close vicinity and the Dll4 (endothelium) / Notch (B-CPC) pair is critically involved in regulating the equilibrium of the immature state versus the differentiation response.

Additionally, genome-wide screens and multi-omics approaches have identified a number of potential regulators of stem cell function, including genes with established roles in transcriptional regulation, cell growth and differentiation, as well as genes whose function is either largely unknown or remains to be validated in the context of stem cell biology, such as the Dido gene.

The Dido locus is strongly expressed in stem cells, which decreases during development and in somatic cells; its expression is also very high in iPS (induced pluripotent stem cells) generated from somatic cells. Its presence is nonetheless critical for cell survival. Dido, a gene complex found only in higher vertebrates, encodes three splice variants: Dido1 (the smallest of these), Dido2, and Dido3. Dido3, the largest and most broadly expressed isoform, encodes a nuclear protein that recognizes trimethylated histone H3 lysine 4 through its N-terminal PHD domain; it interacts with centrosomes and the synaptonemal complex in somatic and germ cells, respectively. N-terminal truncation of Dido3 (Dido3DNT) provokes aneuploidy, centrosome amplification, increased incidence of hematological myeloid neoplasms, brain abnormalities, behavioral alterations and metabolic syndrome.

All attempts to date to delete Dido or a mutant with the exon XVI (Dido3E16) deleted in mice, show that the deletion is incompatible with life. Interestingly, stem cells derived from Dido3 mutants do not differentiate in vitro but they retain their capacity for self-renewal. Furthermore, it has been shown that differentiation can be recovered by expression of full-length Dido3. Based on these results, we propose that Dido acts as a switchboard between self-renewal and differentiation (see figure 2). As dedifferentiation and self-renewal are hallmarks of cancer, we have also studied the susceptibility of Dido3E16 MEF (mouse embryonic fibroblasts) to oncogenic insults in vitro. Our research on cancer also incorporates bioinformatics analysis of publicly available data.

Group Leaders

Antonio Bernad

Carlos Martínez-A

Project Leader

Thierry Fischer

Staff Scientists

Julio Gutiérrez

Tirso Pons