A myocardial lineage derives from Tbx18 epicardial cells

Abstract

Understanding the origins and roles of cardiac progenitor cells is important for elucidating the pathogenesis of congenital and acquired heart diseases. Moreover, manipulation of cardiac myocyte progenitors has potential for cell-based repair strategies for various myocardial disorders. Here we report the identification in mouse of a previously unknown cardiac myocyte lineage that derives from the proepicardial organ. These progenitor cells, which express the T-box transcription factor Tbx18, migrate onto the outer cardiac surface to form the epicardium, and then make a substantial contribution to myocytes in the ventricular septum and the atrial and ventricular walls. Tbx18-expressing cardiac progenitors also give rise to cardiac fibroblasts and coronary smooth muscle cells. The pluripotency of Tbx18 proepicardial cells provides a theoretical framework for applying these progenitors to effect cardiac repair and regeneration.

Fate of retinoic acid–activated embryonic cell lineages

“…Using this strategy, we have created a RA-responsive Cre line, and shown through crosses with the R26R reporter strain that, at early embryonic stages, it results in a pattern of activity virtually identical to that of the lacZ transgene originally created by Rossant et al (1991), and driven by the same RARE-hsp68 composite promoter. As observed for other Cre;R26R studies (e.g., Jiang et al, 2000;Zhang et al, 2003;Huynh et al, 2007;Cai et al, 2008), lacZ activity is stably inherited in RARE-Cre;R26R double transgenic mice, allowing a lineage tracing of the Cre-excised cells. The RARE-Cre transgene described herein will thus be a useful tool for any future work aiming to map the distribution of retinoid-sensitive cell lineages in specific developing systems.…”

“…This correlates with ''late'' effects of RA in regulating myocardial compact zone growth by inducing growth factor signaling and/or cardiomyocyte differentiation (Merki et al, 2005;Lin et al, 2010), and potentially in regulating the epicardial to myocardial lineage conversion (Cai et al, 2008;Zhou et al, 2008). It is noteworthy that a large part of the myocardium (i.e.…”

“…As in other murine lineage studies (e.g., Jiang et al, 2000;Zhang et al, 2003;Huynh et al, 2007;Cai et al, 2008), our strategy uses an ''effector'' transgene driving expression of the Cre recombinase upon RA activation, and a reporter line (the R26R reporter) expressing a functional lacZ gene after Cre-dependent excision of a STOP sequence (Soriano, 1999). We generated transgenic mice in which Cre is driven by the same RARE-hsp68 sequence as in the ''parental'' RARE-hsp68-lacZ transgene (Rossant et al, 1991), and crossed these with R26R reporter mice.…”

“…These include (i) the ''first heart field'' or cardiac crescent formed from mesoderm emerging from the primitive streak (Garcia-Martinez and Schoenwolf, 1993;Tam et al, 1997); (ii) the ''second heart field'' originating from pharyngeal mesoderm (Buckingham et al, 2005); (iii) the (pro)epicardium, a population originating and giving rise to coronary vasculature, myocardial fibroblasts and to a distinct cardiomyocytic lineage (Cai et al, 2008;Zhou et al, 2008), and (iv) the ''cardiac'' neural crest, a subset of post-otic neural crest cells migrating through the third to sixth branchial arches and participating to the development of the aortic arches and aorticopulmonary septum (reviewed by Rochais et al, 2009). All these lineages have been reported to be influenced by embryonic RA (Hochgreb et al, 2003;Ryckebusch et al, 2008;Sirbu et al, 2008;Dupe and Pellerin, 2009), although recent studies implicate the second heart field (Ryckebusch et al, 2008;Sirbu et al, 2008) and the epicardium (Merki et al, 2005;Lin et al, 2010) as the main sites of RA signaling.…”

The mysterious origins of coronary vessels

“…The mainstream view of coronary artery formation from PE-derived ECs has been re-evaluated over the past decade through the use of Cre-LoxP genetic lineage-tracing approaches in mice [4][5][6][7]. Several different mouse Cre lines that label populations within the PE were developed.…”