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Kitcre knock-in mice fail to fate-map cardiac stem cells

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Figure 1: Kitcre genetic lineage cell tracking tags only a minimal fraction of CSCs in vivo and in vitro.
Figure 2: The Wcre allele impairs c-Kitpos adult CSC myogenic and regenerative properties.

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References

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Contributions

D.T. and B.N.-G. designed the research studies, analysed data and wrote the manuscript. C.V., I.A., E.C., M.S., F.M., T.M., F.F., E.D.G., E.I., P.M., V.A. and K.U. conducted the experiments, acquired and analysed data. F.C., A.T. and P.V. conducted RNA-sequencing experiments and analysed bioinformatic data. R.L., A.M.I., D.S. and C.I. contributed reagents. All authors approved the manuscript.

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Correspondence to Bernardo Nadal-Ginard or Daniele Torella.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 The KitCreER(T2) allele reduces c-Kit expression and does not fate-map c-Kit-expressing CSCs with a short-term tamoxifen diet.

a, Kit mRNA (left) and c-Kit protein (right) levels in all c-Kit-expressing cells isolated from bone marrow (BM) and heart of wild-type Kit+/+, heterozygous KitCreER(T2)/+ and KitCreGFPnls/+ mice. Representative of n = 5 bone marrow samples and hearts. *P < 0.05 versus wild-type Kit+/+ mice. b, qPCR (left) cumulative data and representative western blot (right) analysis show that Kit mRNA and c-Kit protein levels in cardiomyocyte-depleted FACS-sorted CD45posCD31posc-Kitpos cardiac cells versus CD45negCD31negc-Kitpos cardiac cells. Representative of n = 5 hearts. *P < 0.05 versus CD45posCD31posc-Kitpos cardiac cells. c, d, Kit mRNA (c) and c-Kit protein (d) expression levels in different cell populations from wild-type mice. Representative of n = 4 biological replicates. *P < 0.05 versus mast cells; #P < 0.05 versus HSCs in c. c, Kit transcript levels are verified over Kit mRNA absence in negative control (Neg CTRL), which are triple-negative-sorted CD45negCD31negc-Kitneg cardiac cells. e, Western blot analysis showing CreER(T2) expression in bone marrow mast cells; CreER(T2) expression is only faintly detectable in freshly isolated CD45negCD31negc-Kitpos CSCs from KitCreER(T2)/+ mice. Representative of n = 3 biological replicates. f, cre mRNA levels in bone marrow mast cells, bone marrow Linneg cells and CSCs from KitCreER(T2)/+ and KitCreGFPnls/+ mice. Representative of n = 5 mice. *P < 0.05 versus mast cells; #P < 0.05 versus bone marrow. gl, FACS analysis showing recombination efficiency in isolated bone marrow and cardiac cells from double-mutant KitCreER(T2)/+:Rosa26mT/mG/+ mice treated with standard tamoxifen (Tam) diet (400 mg per kg diet) for 14 days. g, Fraction of Cre-recombined GFP-expressing cells in the monocyte–lymphocyte gate of total bone marrow cells after 14 days of tamoxifen diet. No recombination is evidence in the absence of tamoxifen. h, Fraction of Cre-recombined GFP-expressing cells in c-Kitpos bone marrow cells after 14 days of tamoxifen diet. i, Gating of the Linneg bone marrow cells for the long-term repopulating LinnegSca-1posc-Kitpos (LSK) HSCs showing that only <5% HSCs showed recombination. j, The majority of bone marrow mast cells showed recombination and expressed GFP after 14 days of tamoxifen diet. k, The 14-day tamoxifen regime recombined ≤20% of the cardiomyocyte-depleted total c-Kitpos cardiac cell population. l, All GFP-recombined c-Kitpos cardiac cells were positive for CD45, CD31 (CD45pos, CD31pos) or both, representing cardiac mast cells or endothelial (progenitor) cells. Only a negligible fraction, <1%, of the c-Kitlow and CSC-enriched Linneg CD45negCD31negc-Kitpos cardiac cells showed recombination and expression of GFP. gl, Representative of n = 5 bone marrow samples and hearts. Data are mean ± s.d.

Extended Data Figure 2 Fate-map tracking of c-Kitpos cells using Kitcre mice.

a, Mice with KI in exon 1 of the Kit locus targeted to express tamoxifen-inducible Cre recombinase (CreER(T2)) were crossed with Cre-reporter Rosa26 mice (Rosa26mT/mG); the double-heterozygous mice were fed tamoxifen for four months. b, Confocal images (left) and FACS plots (right) show that KitCreER(T2) allele recombines in c-Kit-expressing Leydig cells and spermatogonia (and their derivatives within the seminiferous tubule) to express GFP in the testis whereas GFP expression was induced in around 40% of c-Kitpos cells of this tissue. Representative of n = 5 mice. Scale bar, 50 μm. c, FACS plot of total bone marrow (with lymphocyte–monocyte gating strategy, left) of double-mutant KitCreER(T2)/+:Rosa26mT/mG/+ showing GFP expression in approximately 80% of cells, but no signal in the absence of tamoxifen. In particular, ≥70% of all c-Kit-antibody-detected cells were GFPpos. Representative of n = 5 bone marrow samples. d, Most bone marrow mast cells (c-Kit expression, left) showed recombination and expressed GFP. e, Only a fraction (<35%) of the long-term LSK HSCs expressed GFP. f, Representative confocal images of cardiac cross-sections from KitCreER(T2)/+:Rosa26mT/mG/+ mice treated with tamoxifen diet for four months show that Cre-dependent recombination-induced GFP expression is detectable only in a fraction (around 60%) of non-cardiomyocyte c-Kit-labelled cardiac cells. Scale bars, 20 μm. Representative of n = 5 mice. g, Mice with Kit exon 1 locus KI to express Cre recombinase and GFP with a nuclear localization sequence (GFPnls) behind an internal ribosome entry site (IRES) were crossed to Cre reporter Rosa26 mice (Rosa26mT/mG) for lineage tracing. h, Confocal images (left) and FACS plots (right) show that the KitCreGFPnls allele recombines in Leydig cells and spermatogonia in the testis to become GFPpos whereas the overall recombination in the testis was approximately 80% of the c-Kitpos cells. Scale bars, 50 μm. Note that the majority of recombined cells still express mT. Representative of n = 5 mice. i, FACS plot of total bone marrow cells from double-mutant KitCreGFPnls/+:Rosa26mT/mG/+ mice showing GFP expression in more than 90% of cells. Approximately 90% of total c-Kit-antibody-detected cells were GFPpos. j, A majority of LSK HSCs expressed GFP. Representative of n = 5 bone marrow samples.

Extended Data Figure 3 Fate-map tracking of c-Kitpos CSCs using Kitcre mice.

FACS analysis showing recombination efficiency in isolated cardiomyocyte-depleted cardiac cells from double-mutant KitMCM/+:Rosa26mT/mG/+ mice treated with a standard tamoxifen diet (400 mg per kg diet) for 21 days (n = 5 mice). a, After 21 days of tamoxifen diet, less than 2% of total cardiac cells showed recombination and induction of GFP. Note that all the identified MCM-recombined GFPpos cells were also still mTpos. Approximately 10% of the cardiomyocyte-depleted c-Kitpos cardiac cell population showed recombination and expressed GFP. b, Independently of the level of c-Kit expression, almost all recombined GFPpos cells were CD31pos (around 85%) and CD45pos (about 25%). Thus, a standard tamoxifen regime with a widely used pulse period only genetically recombines lineage-committed cells (endothelial or immune cells) within the heart. c, All GFP-expressing recombined c-Kitpos cardiac cells were CD45pos, CD31pos or both, representing cardiac mast cells or endothelial (progenitor) cells. Only a negligible fraction, <1%, of the c-Kitlow and CSC-enriched LinnegCD45negCD31negc-Kitpos cardiac cells showed recombination and induction of GFP expression. ac, Representative of n = 4 hearts. df, KitCreGFPnls/+ mice were crossed with B6;129S6-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (abbreviated as Rosa26floxed-stop-tdTomato) mice that have a targeted mutation in the Gt(ROSA)26Sor locus with a loxP-flanked STOP cassette preventing transcription of a CAG-promoter-driven red fluorescent protein variant (tdTomato), which is expressed following Cre-mediated recombination. d, Around 20% of total cardiac cells and about 70% of c-Kitpos cardiac cells from these mice are tdTomatopos. e, Around 70% of lineage-committed endothelial/mast cell (CD45posCD31posc-Kitpos) cardiac cells showed recombination and expressed tdTomato, whereas less than 10% of the CSC-enriched CD45negCD31negc-Kitpos showed recombination and were tdTomatopos. d, e, Representative of n = 5 hearts. f, Confocal image showing recombined tdTomatopos cardiomyocytes in the ventricular myocardium of 8–12-week-old KitCreGFPnls/+:Rosa26floxed-stop-tdTomato/+ mice. Representative of n = 3 hearts. Scale bar, 50 μm.

Extended Data Figure 4 Wcre allele KI and resulting Kit heterozygosity impair CSC biology and myogenic potential in vitro.

a, Serum-induced 24 h BrdU incorporation by freshly isolated WCreGFPnls/+ CSCs compared to wild-type CSCs. *P < 0.05 versus T0; #P < 0.05 versus wild-type CSCs. Clonal efficiency of freshly isolated WCreGFPnls/+ CSCs compared to wild-type CSCs. *P < 0.05 versus wild-type CSCs. WCreGFPnls/+ CSCs formed fewer cardiospheres than wild-type CSCs. The number of cardiospheres is expressed as a percentage of 1 × 105 plated cells. *P < 0.05 versus wild-type CSCs. Single-cell-cloned WCreGFPnls/+ CSCs re-cloned at lower efficiency than wild-type CSCs. *P < 0.05 versus wild-type CSCs. n = 5 experiments. b, Heat map of RNA-sequencing profile of the 2,425 downregulated and 2,870 upregulated genes for the comparison of WCre and wild-type CSCs and their gene ontology clustering for specific gene function. n = 3 of biological replicates. c, Functional categorization by ingenuity pathway analysis (IPA) of the downregulated and upregulated genes by RNA sequencing in the comparison between WCre CSC (from KitCreER(T2)/+ mice) and wild-type CSC clones. Histogram represents the most significant canonical pathways generated using IPA software. The ratio was calculated by dividing the number of genes from our dataset that map to each single pathway by the total number of genes included into the canonical pathway. b, c, Mean of n = 3 biological replicates. d, PCR analysis with two different pair of BAC primers showing BACKit expression in mT-WCre CSCs. Kit gene primers were used as control. n = 3 biological replicates. e, qPCR data showing Kit DNA copy number in BAC-naive mT-WCre CSCs and mT-BACKitWCre CSCs. Representative of n = 3 biological replicates. f, Clonal efficiency of mT-BACKitWCre CSCs, mT-WCre CSCs and mT-WT CSCs. *P < 0.05 versus all other treatments. n = 5 biological replicates. g, Cardiosphere formation of mT-BACKitWCre CSCs, mT-WCre CSCs and mT-WT CSCs. *P < 0.05 versus all other treatments. n = 5 biological replicates. h, Bar graph and confocal images of cTnI expression in cardiospheres from cloned mT-WT CSCs, mT-WCre CSCs and mT-BACKitWCre CSCs after 14 days in myogenic medium. *P < 0.05 versus all other treatments. Representative of n = 5 biological replicates. Scale bar, 50 μm. Data are mean ± s.d.

Extended Data Figure 5 Kitcre-KI hampers cardiac regeneration and repair after myocardial infarction.

To test the effect of the Kitcre-KI mutations on cardiac regeneration in vivo, 10-week-old female KitCreGFPnls/+:Rosa26mT/mG/+ double-heterozygous mice and Rosa26mT/mG/+ heterozygous controls were subjected to myocardial infarction (MI) by permanent ligation of the left coronary artery followed by systemic BrdU administration through mini-osmotic pumps. KitCreGFPnls/+-KI mice were used instead of tamoxifen-inducible KitCreER(T2)/+-KI mice, because of their highest Kitcre-induced recombination and to avoid possible confounding effects related to tamoxifen (and tamoxifen-induced Cre) toxicity in vivo9. KitCreGFPnls/+:Rosa26mT/mG/+ double-heterozygous females had to be used, because in our hands the acute mortality of myocardial infarction in sibling males was ≥75% whereas it was around 30% in the Rosa26mT/mG/+ heterozygous controls. Additionally, around 50% of KitCreGFPnls/+:Rosa26mT/mG/+ males and about 30% of KitCreGFPnls/+:Rosa26mT/mG/+ females showed spontaneous alterations of cardiac function at baseline before myocardial infarction and had to be excluded. a, Light microscopy images showing Masson staining of infarcted hearts from c-Kit wild-type control Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice. Representative of n = 6 mice per group. b, Infarct size assessment 28 days after coronary ligation in Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice. *P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. c, Representative confocal microscopy images of BrdU incorporation in the border zone of infarcted hearts from Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice. Scale bar, 50 μm. d, Number of newly generated BrdUpos cardiomyocytes in sham and infarcted (MI) Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice 28 days after sham or myocardial infarction surgery. *P < 0.05 versus sham; #P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. e, f, Representative confocal microscopy images of GFPpos cardiomyocytes in the border zone of infarcted hearts from KitCreGFPnls/+:Rosa26mT/mG/+ mice. Note that in f GFPpos cardiomyocytes are BrdUneg. Scale bar, 50 μm. g, Bar graph with cumulative data showing the number of GFPpos cardiomyocytes in sham and infarcted KitCreGFPnls/+:Rosa26mT/mG/+ mice 28 days after surgery. h, Representative confocal images of cardiac cross-sections showing higher cardiomyocyte hypertrophy in KitCreGFPnls/+:Rosa26mT/mG/+ compared to Kit+/+:Rosa26mT/mG/+ mice 28 days after myocardial infarction. WGA, wheat-germ agglutinin. Scale bar, 50 μm. i, Cardiomyocyte size in Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice. *P < 0.05 versus sham; #P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. j, Arteriolar density in the infarct border zone of Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice 28 days after myocardial infarction. *P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. k, Capillary density in the infarct border zone of Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice 28 days after myocardial infarction. *P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. l, Echocardiography assessment of left ventricular function 28 days after myocardial infarction in Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice. *P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. LVEDD, left ventricle end diastolic diameter; LVESD, left ventricle end systolic diameter; EF, ejection fraction; FS, fractional shortening. m, Representative echo images and longitudinal and circumferential strain traces in long and short axis, from Kit+/+:Rosa26mT/mG/+ and KitCreGFPnls/+:Rosa26mT/mG/+ mice at baseline (Base) and 28 days after myocardial infarction. n, Longitudinal and circumferential strain values in Kit+/+:Rosa26mT/mG/+ versus KitCreGFPnls/+:Rosa26mT/mG/+ mice at baseline and 28 days after myocardial. *P < 0.05 versus baseline; #P < 0.05 versus Kit+/+:Rosa26mT/mG/+ mice. n = 6 mice per group. Data are mean ± s.d.

Extended Data Figure 6 Wcre-null allele hampers CSC regenerative potential after myocardial infarction and neomyogenesis, which is independent from cell fusion.

a, Cumulative data of CSC-derived mTpos cardiomyocytes from female C57BL/6J wild-type mice 28 days after myocardial infarction treated with either saline (n = 6 mice) or with the indicated CSC types (n = 6 mice per group). *P < 0.05 versus all other treatments. b, Representative confocal image of a CSC-derived newly formed mTpos cardiomyocyte in mT-Wcre CSC-injected mice 28 days after myocardial infarction. Scale bar, 30 μm. c, Cumulative data of arteriolar density in the infarct border zone of saline-, mT-WT CSC- or mT-WCre CSC-treated female C57BL/6J wild-type mice 28 days after myocardial infarction. *P < 0.05 versus all other treatments. d, Cumulative data of capillary density in the infarct border zone of saline-, mT-WT CSC- or mT-WCre CSC-treated female C57BL/6J wild-type mice 28 days after myocardial infarction. *P < 0.05 versus all other treatments. bd, Number of mice per group as indicated in a. eg, Cumulative data of CSC-derived mTpos cardiomyocytes (e), arteriolar density (f) and capillary density (g) in the infarct border zone of female wild-type C57BL/6J mice 28 days after myocardial infarction treated with saline (n = 6), mT-WCre CSCs (n = 6) or mT-BACKitWCre CSCs (n = 6). *P < 0.05 versus all other treatments. h, Schematic of study design to assess CSC fusion with hosting cardiomyocytes. Transgenic (Tg) Myh6-MerCreMer (TgMyh6-MCM) female (n = 3) mice that carry a transgenic cardiomyocyte-restricted tamoxifen-inducible cre gene construct, had were subjected to myocardial infarction by coronary ligation. Right after coronary ligation, mice were treated by tail-vein injection with wild-type clonal mTpos CSCs (mT-WT CSCs). Mice were fed with a tamoxifen diet for four weeks. The mT-WT CSCs were isolated from Rosa26mT/mG male mice and cloned. Therefore, these clonal cells and their progeny constitutively express membrane Tomato (mTpos), which switches to express membrane GFP (becoming mGpos) when recombined in response to Cre recombinase. The injection of mT-WT CSCs in TgMyh6-MCM mice tests directly whether new cardiomyocytes are exclusively the progeny of the mT-WT CSCs injected, in which case these cells should be red (mTpos), or the result of cell fusion of the injected cells with host cardiomyocytes, in which case the cells should be yellow (mTpos and mGpos together show as yellow) or only green (mGpos). Indeed, if the putative new cardiomyocytes were not newly generated, but the product of the fusion of the injected cells with the host cardiomyocytes, these fused cells should be yellow or green. Tamoxifen activates Cre only in the host cardiomyocytes of TgMyh6-MCM mice and the recombination induces the expression of mG only if the injected reporter-switchable CSCs fuse with the host cardiomyocytes. Thus, the recombined host cardiomyocytes will be either mTpos and mGpos (yellow) or mGpos (green), the latter depending on the dilution time of mT expression after recombination. On the other hand, mGnegmTpos cardiomyocytes can only be the direct progeny of the injected CSCs with no fusion to host cardiomyocytes. i, Representative confocal microscopy images of CSC-derived mTpos cardiomyocytes in the border zone (3.0 ± 0.5%) of TgMyh6-MCM mice with myocardial infarction treated with mT-WT CSCs and fed with a tamoxifen diet. It is evident that labelled cardiomyocytes in the infarct border zone were mTpos but mGneg as expected for the cardiomyocyte-differentiated progeny of the injected CSCs, which excludes cell fusion as a relevant mechanism for the appearance of these new muscle cells after myocardial infarction. Scale bar, 50 μm. Note, the level of baseline red or green autofluorescent cardiomyocytes in un-transplanted mice resulting from the staining protocols was <0.005%. None of these weak apparently positive signals had the typical membrane localization expected for the membrane-targeted dTomato and GFP Cre reporters. j, The mT and mG signal gains for the confocal images in i were set to appropriate positive controls using double transgenic TgMyh6-MCM::Rosa26mT/mG mice fed with a normal diet (no tamoxifen) or tamoxifen diet. Scale bar, 50 μm. Data are mean ± s.d.

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High magnification of a beating wild type CSC-derived Cardiosphere

This video shows a beating wild type CSC-derived Cardiosphere in high magnification. (MP4 863 kb)

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Vicinanza, C., Aquila, I., Cianflone, E. et al. Kitcre knock-in mice fail to fate-map cardiac stem cells. Nature 555, E1–E5 (2018). https://doi.org/10.1038/nature25771

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