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Ckit Cardiac Progenitors of Neural Crest Origin

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Ckit Cardiac Progenitors of Neural Crest Origin + cKit cardiac progenitors of neural crest origin Konstantinos E. Hatzistergosa, Lauro M. Takeuchia, Dieter Saurb, Barbara Seidlerb, Susan M. Dymeckic, Jia Jia Maic, Ian A. Whitea, Wayne Balkana, Rosemeire M. Kanashiro-Takeuchia,d, Andrew V. Schallye,1, and Joshua M. Harea,1 aInterdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136; bDepartment of Internal Medicine, Mediziniche Klinik und Policlinik Der Technischen Universitat Munchen, Munich 81675, Germany; cDepartment of Genetics, Harvard Medical School, Boston, MA 02115; dDepartment of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, Miami, FL 33136; and eDepartment of Pathology and Medicine, University of Miami School of Medicine and Veterans Affairs Medical Center, Miami, FL 33125 Contributed by Andrew V. Schally, August 29, 2015 (sent for review April 27, 2015; reviewed by Roger Joseph Hajjar) The degree to which cKit-expressing progenitors generate cardio- we demonstrate that cKit marks CNCs. Furthermore, we show that myocytes in the heart is controversial. Genetic fate-mapping studies their relatively small contribution to myocardium during embryogen- suggest minimal contribution; however, whether or not minimal esis is not related to poor cardiomyogenic capacity, but rather to contribution reflects minimal cardiomyogenic capacity is unclear be- changes in the cardiac activity of the bone morphogenetic protein cause the embryonic origin and role in cardiogenesis of these pro- (BMP) pathway that prevent their differentiation into cardiomyocytes. genitors remain elusive. Using high-resolution genetic fate-mapping approaches with cKitCreERT2/+ and Wnt1::Flpe mouse lines, we show Results kit kit that cKit delineates cardiac neural crest progenitors (CNC ). CNC Genetic Lineage-Tracing of cKit+ CPs. We used a well-characterized + + possess full cardiomyogenic capacity and contribute to all CNC de- cKitCreERT2/ mouse line to lineage-trace cKit CPs (23–25). + rivatives, including cardiac conduction system cells. Furthermore, by cKitCreERT2/ are healthy, fertile, and express the white spotting modeling cardiogenesis in cKitCreERT2-induced pluripotent stem cells, kit phenotype (12, 23, 24, 26) (Fig. 1A). we show that, paradoxically, the cardiogenic fate of CNC is regu- We first investigated whether cKit marks mesodermal CPs (e.g., lated by bone morphogenetic protein antagonism, a signaling path- first- or second-heart field CPs; or primitive hemogenic lineage) way activated transiently during establishment of the cardiac (1), by administering pregnant mice carrying cKitCreERT2;IRG em- crescent, and extinguished from the heart before CNC invasion. To- + bryos with tamoxifen (TAM) from embryonic days (E)7.5 to E8.5 gether, these findings elucidate the origin of cKit cardiac progenitors (Fig. 1B and Table S1). At E18.5, EGFP expression was detected in and suggest that a nonpermissive cardiac milieu, rather than minimal MEDICAL SCIENCES kit mesodermal cells (13, 14, 21, 26), including gonads, blood, and cardiomyogenic capacity, controls the degree of CNC contribution lungs (Fig. 1 C and D). At this stage of labeling (21), EGFP was to myocardium. + rarely detected in the heart, and EGFP heart cells were non- cardiomyocytes with rare colocalization with the cardiac tran- cardiac stem cells | cardiac neural crest | cardiomyogenesis | BMP signalling scription factor Gata4 (Fig. 1 E and F). Next, to test whether cKit marks other cardiomyogenic line- eart development is a highly regulated process during which ages (e.g., proliferating cardiomyocytes; or CPs of the epicardial, Hcell lineage diversification and growth programs are dynam- CNC, and definitive hemogenic lineages) (1), we administered ically coordinated in temporal and spatial manners (1). These TAM to pregnant mice at selected time points during E9.5–E12.5 programs are activated sequentially, in parallel, or intersect to give rise to distinct heart domains. For example, the myocardial lineage Significance originally develops from cardiac progenitors (CPs) of mesodermal origin (2–5), which form the first and second heart fields. How- ever, later during morphogenesis, the cardiomyogenic program A high-resolution genetic lineage-tracing study in mice reveals diverges and activates cardiomyocyte proliferation signals, along that cKit identifies multipotent progenitors of cardiac neural with CPs from the hemogenic endothelium, epicardial, cardio- crest (CNC) origin. Normally, the proportion of cardiomyocytes pulmonary, and cardiac neural crest (CNC) lineages, to produce produced from this lineage is limited, not because of poor new cardiomyocytes (1, 6–11). Gauging the relative contribution differentiation capacity as previously thought, but because of of each lineage for scaling their cardiomyogenic—and consequently stage-specific changes in the activity of the bone morphoge- therapeutic—capacity is a challenge. For example, many of the CP netic protein pathway. Transient bone morphogenetic protein antagonism efficiently directs mouse iPSCs toward the CNC lineages are heterogeneous and incompletely characterized, and + therefore cannot always be traced under a straightforward genetic lineage and, consequently, the generation of cKit CNCs with fate-mapping experiment. Furthermore, it is unknown whether and full capacity to form cardiomyocytes and other CNC derivatives how changes in the cardiac milieu (i.e., morphogens, tissue com- in vitro. These findings resolve a long-standing controversy position, and size) regulate the final proportions of heart muscle regarding the role of cKit in the heart, and are expected to lead derived from each lineage. to the development of novel stem cell-based therapies for the cKit is a receptor tyrosine kinase that marks several cell lineages, prevention and treatment of cardiovascular disease. including neural crest (NC), hematopoietic, and germ-line stem cells – Author contributions: K.E.H., A.V.S., and J.M.H. designed research; K.E.H., L.M.T., and (12 15). Following the seminal description by Beltrami et al. (16) of R.M.K.-T. performed research; K.E.H., D.S., B.S., S.M.D., J.J.M., I.A.W., and J.M.H. contrib- clusters of cKit cells in the postnatal mammalian heart, several uted new reagents/analytic tools; K.E.H., L.M.T., R.M.K.-T., and J.M.H. analyzed data; and laboratories, including ours, suggested that cKit marks CPs (16–19), K.E.H., D.S., W.B., A.V.S., and J.M.H. wrote the paper. a finding that led to the clinical testing of these cells for heart repair Reviewers included: R.J.H., Mount Sinai School of Medicine. (20). Recently, a straightforward genetic fate-mapping study showed Conflict of interest statement: K.E.H. and J.M.H. report having a patent for cardiac cell- that a relatively small proportion of murine myocardium is derived based therapy. K.E.H. and J.M.H. own equity in Vestion Inc. and are members of the + from cKit CPs, leading to the conclusion that the cardiomyogenic scientific advisory board and consultants of Vestion, Inc. J.M.H. is a board member of + Vestion Inc. Vestion Inc. did not participate in funding this work. The other authors report capacity of cKit CPs is functionally insignificant (21). However, the + no conflicts. identity of cKit CPs and the mechanisms controlling their differ- 1To whom correspondence may be addressed. Email: [email protected] or andrew. entiation into cardiomyocytes remain controversial (22). Here, by [email protected]. using a high-resolution genetic lineage-tracing strategy, as well as This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. induced pluripotent stem cell (iPSC)-based models of cardiogenesis, 1073/pnas.1517201112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1517201112 PNAS | October 20, 2015 | vol. 112 | no. 42 | 13051–13056 Downloaded by guest on October 1, 2021 CreERT2/+ Fig. 1. cKit lineage-tracing. (A) Phenotype CreERT2/+ of cKit mice. (B) Summary of the experi- mental design. (C–F) administration of TAM during E7.5–E8.5 (n = 10) marks testicular (C, arrowheads), pulmonary (D) and, rarely, immature cells in the myocardium (E and F, arrowheads). (G–J) Live tissue CreERT2/+ CreERT2 imaging of cKit (G), IRG (H), and cKit ; IRG (I) E18.5 littermates subjected to TAM during E9.5–E11.5 (n = 7). Widespread EGFP epifluorescence in ventricles and atria (I and J), lungs (J), OFT (J, arrow), epicardium (J, arrowheads). (K–N) Lineage- tracing in cKitCreERT2;R26RlacZ mice (n = 8). (O)Sum- mary of cKit genetic fate-mapping. Panels F and J are confocal tile-scans. Panels K–N are photomerged im- age tiles. (Scale bars, 10 μminD and F;200μminJ; 500px in K–N.) (Magnification, 100× in C, E,andG–I.) (Table S1). Cre-mediated recombination resulted in EGFP tdTomato in various NC-derived tissues of E12.5 Wnt1-Cre;RC:: expression in embryonic melanoblasts, craniofacial cells (27), tdTomato embryos, including the NT and the heart, (Fig. S3). How- − + + + neural tube (NT), dorsal root ganglia (DRGs), blood, gastroin- ever, compared with the cKit /tdTomato cells, cKit /tdTomato testinal cells, gonads, and pulmonary cells (Fig. 1 G–J). Unlike population exhibited a weak expression of tdTomato (Fig. S3). the fate-map of E7.5–E8.5 cKit-expressing cells, EGFP epifluor- We therefore performed NC lineage-restricted genetic fate- escence is detected within the cardiac outflow tract (OFT), epi- mapping of cKit. We generated a novel mouse carrying two cardium, and myocardium (Fig. 1 G–J). recombinase systems (Cre-loxP and Flp-FRT), which enables + To rule
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