Sall1 transiently marks undifferentiated heart precursors and regulates their fate

Abstract

Cardiac progenitor cells (CPCs) are a crucial source of cells in cardiac development and regeneration. However, reported CPCs are heterogeneous, and no gene has been identified to transiently mark undifferentiated CPCs throughout heart development. Here we show that Spalt-like gene 1 (Sall1), a zing-finger transcription factor, is expressed in undifferentiated CPCs giving rise to both left and right ventricles. Sall1 was transiently expressed in precardiac mesoderm contributing to the first heart field (left ventricle precursors) but not in the field itself. Similarly, Sall1 expression was maintained in the second heart field (outflow tract/right ventricle precursors) but not in cardiac cells. In vitro, high levels of Sall1 at mesodermal stages enhanced cardiomyogenesis, whereas its continued expression suppressed cardiac differentiation. Our study demonstrates that Sall1 marks CPCs in an undifferentiated state and regulates cardiac differentiation. These findings provide fundamental insights into CPC maintenance, which can be instrumental for CPC-based regenerative medicine.

Cardiac-specific developmental and epigenetic functions of Jarid2 during embryonic development

“…However, Tcf/Lef1-mediated Wnt signaling regulates the transcription of cardiac factors, such as Isl1, Mesp1, and Anf, and cardiac development (33)(34)(35). In addition, mutations of Sall1 cause Townes-Brocks syndrome in humans with heart anomalies, and Sall1 expresses in the undifferentiated cardiac progenitor cell (36,37). Sall1 expression was significantly increased in Jarid2 Nkx hearts.…”

Copy number variants in hypoplastic right heart syndrome

“…A deletion overlapping RBL2 has been reported in an infant with atrioventricular septal defect (Tang et al, ). NKD1 has been shown to be a passive inhibitor of the Wnt signaling pathway and SALL1 functions as transcriptional activator of the Wnt signaling pathway (Angonin & Van Raay, ; Morita et al, ; Sato et al, ). MYLK3 is expressed in the embryonic heart and upregulation of MYLK3 has been identified in failing human myocardia (Chan et al, ; Tobita et al, ).…”

“…RBL2 maintains the overall chromatin structure in a cell, particularly the structure of constitutive heterochromatin, which is stabilized by histone methylation and deletions in this region have been associated with CHD (Tang et al, ). SALL1 has been reported to act as a regulator of cardiac progenitor cells defining their fate (Morita et al, ). Mouse studies have shown that Sall1 is expressed in the mesoderm at preheart field stages and in secondary heart field cells from heart field stages before the formation of the outflow tract (OFT) and the right ventricle (Morita et al, ).…”

“…SALL1 has been reported to act as a regulator of cardiac progenitor cells defining their fate (Morita et al, ). Mouse studies have shown that Sall1 is expressed in the mesoderm at preheart field stages and in secondary heart field cells from heart field stages before the formation of the outflow tract (OFT) and the right ventricle (Morita et al, ). SALL1 has also been suggested to be implicated in Wnt signaling acting as an enhancer through heterochromatin localization (Sato et al, ).…”

Cardiac septation in heart development and evolution

“…The FHF, positive for Tbx5 and Hcn4 , gives rise to the left ventricle and parts of the atria (Bruneau et al., ; Liang et al., ; Später et al., ). While the SHF, positive for Islet1 , Tbx1 , Tbx20 , Sall1, Mef2c‐AHF enhancer and secreted molecules encoded by Fgf8 and Fgf10 , gives rise to the right ventricle, the OFT and parts of the atria (Cai et al., ; Kelly, Brown, & Buckingham, ; Morita et al., ; Takeuchi et al., ; Verzi, McCulley, De Val, Dodou, & Black, ; Yamagishi et al., ). The facts mentioned above show that the ventricular septum is formed at the boundary of the FHF and SHF in mammals.…”