Skip to main content
SpringerLink
Log in

Dual recombinases-based genetic lineage tracing for stem cell research with enhanced precision

  • Review
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Stem cell research has become a hot topic in biology, as the understanding of stem cell biology can provide new insights for both regenerative medicine and clinical treatment of diseases. Accurately deciphering the fate of stem cells is the basis for understanding the mechanism and function of stem cells during tissue repair and regeneration. Cre-loxP-mediated recombination has been widely applied in fate mapping of stem cells for many years. However, nonspecific labeling by conventional cell lineage tracing strategies has led to discrepancies or even controversies in multiple fields. Recently, dual recombinase-mediated lineage tracing strategies have been developed to improve both the resolution and precision of stem cell fate mapping. These new genetic strategies also expand the application of lineage tracing in studying cell origin and fate. Here, we review cell lineage tracing methods, especially dual genetic approaches, and then provide examples to describe how they are used to study stem cell fate plasticity and function in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anastassiadis, K., Fu, J., Patsch, C., Hu, S., Weidlich, S., Duerschke, K., Buchholz, F., Edenhofer, F., and Stewart, A.F. (2009). Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice. Dis Model Mech 2, 508–515.

    Article  CAS  PubMed  Google Scholar 

  • Awatramani, R., Soriano, P., Rodriguez, C., Mai, J.J., and Dymecki, S.M. (2003). Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation. Nat Genet 35, 70–75.

    Article  CAS  PubMed  Google Scholar 

  • Axelrod, D. (1979). Carbocyanine dye orientation in red cell membrane studied by microscopic fluorescence polarization. Biophys J 26, 557–573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basil, M.C., Katzen, J., Engler, A.E., Guo, M., Herriges, M.J., Kathiriya, J. J., Windmueller, R., Ysasi, A.B., Zacharias, W.J., Chapman, H.A., et al. (2020). The cellular and physiological basis for lung repair and regeneration: past, present, and future. Cell Stem Cell 26, 482–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beltrami, A.P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., Kasahara, H., Rota, M., Musso, E., Urbanek, K., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776.

    Article  CAS  PubMed  Google Scholar 

  • Bowling, S., Sritharan, D., Osorio, F.G., Nguyen, M., Cheung, P., Rodriguez-Fraticelli, A., Patel, S., Yuan, W.C., Fujiwara, Y., Li, B.E., et al. (2020). An engineered CRISPR-Cas9 mouse line for simultaneous readout of lineage histories and gene expression profiles in single cells. Cell 181, 1693–1694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brash, J.T., Bolton, R.L., Rashbrook, V.S., Denti, L., Kubota, Y., and Ruhrberg, C. (2020). Tamoxifen-activated CreERT impairs retinal angiogenesis independently of gene deletion. Circ Res 127, 849–850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cano, A., Pérez-Moreno, M.A., Rodrigo, I., Locascio, A., Blanco, M.J., del Barrio, M.G., Portillo, F., and Nieto, M.A. (2000). The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2, 76–83.

    Article  CAS  PubMed  Google Scholar 

  • Conklin, E.G. (1905). The Organization and Cell-lineage of the Ascidian Egg. Philadelphia: Academy of Natural Sciences.

    Google Scholar 

  • Dawn, B., Stein, A.B., Urbanek, K., Rota, M., Whang, B., Rastaldo, R., Torella, D., Tang, X.L., Rezazadeh, A., Kajstura, J., et al. (2005). Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 102, 3766–3771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng, X., Zhang, X., Li, W., Feng, R.X., Li, L., Yi, G.R., Zhang, X.N., Yin, C., Yu, H.Y., Zhang, J.P., et al. (2018). Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114–122.e3.

    Article  CAS  PubMed  Google Scholar 

  • Dymecki, S.M., Ray, R.S., and Kim, J.C. (2010). Mapping cell fate and function using recombinase-based intersectional strategies. Method Enzymol 477, 183–213.

    Article  CAS  Google Scholar 

  • Ellison, G.M., Vicinanza, C., Smith, A.J., Aquila, I., Leone, A., Waring, C. D., Henning, B.J., Stirparo, G.G., Papait, R., Scarfò, M., et al. (2013). Adult c-kitpos cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154, 827–842.

    Article  CAS  PubMed  Google Scholar 

  • Engleka, K.A., Manderfield, L.J., Brust, R.D., Li, L., Cohen, A., Dymecki, S.M., and Epstein, J.A. (2012). Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 110, 922–926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farago, A.F., Awatramani, R.B., and Dymecki, S.M. (2006). Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps. Neuron 50, 205–218.

    Article  CAS  PubMed  Google Scholar 

  • Feil, R., Wagner, J., Metzger, D., and Chambon, P. (1997). Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun 237, 752–757.

    Article  CAS  PubMed  Google Scholar 

  • Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M.A., Ye, L., et al. (2015). Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fox, D.T., Morris, L.X., Nystul, T., and Spradling, A.C. (2008). Lineage analysis of stem cells. In StemBook. Cambridge: Harvard Stem Cell Institute.

    Google Scholar 

  • Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., et al. (2011). Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43, 34–41.

    Article  CAS  PubMed  Google Scholar 

  • Giangreco, A., Reynolds, S.D., and Stripp, B.R. (2002). Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 161, 173–182.

    Article  PubMed  PubMed Central  Google Scholar 

  • Guy, C.T., Cardiff, R.D., and Muller, W.J. (1992). Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12, 954–961.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Han, X., Wang, Y., Pu, W., Huang, X., Qiu, L., Li, Y., Yu, W., Zhao, H., Liu, X., He, L., et al. (2019). Lineage tracing reveals the bipotency of SOX9+ hepatocytes during liver regeneration. Stem Cell Rep 12, 624–638.

    Article  CAS  Google Scholar 

  • He, L., Li, Y., Li, Y., Pu, W., Huang, X., Tian, X., Wang, Y., Zhang, H., Liu, Q., Zhang, L., et al. (2017). Enhancing the precision of genetic lineage tracing using dual recombinases. Nat Med 23, 1488–1498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henner, A., Ventura, P.B., Jiang, Y., and Zong, H. (2013). MADM-ML, a mouse genetic mosaic system with increased clonal efficiency. PLoS ONE 8, e77672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henning, R.J. (2011). Stem cells in cardiac repair. Future Cardiol 7, 99–117.

    Article  PubMed  Google Scholar 

  • Hogan, B.L.M., Barkauskas, C.E., Chapman, H.A., Epstein, J.A., Jain, R., Hsia, C.C.W., Niklason, L., Calle, E., Le, A., Randell, S.H., et al. (2014). Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holt, C.E., Garlick, N., and Cornel, E. (1990). Lipofection of cDNAs in the embryonic vertebrate central nervous system. Neuron 4, 203–214.

    Article  CAS  PubMed  Google Scholar 

  • Hopper, R.K., Moonen, J.R.A.J., Diebold, I., Cao, A., Rhodes, C.J., Tojais, N.F., Hennigs, J.K., Gu, M., Wang, L., and Rabinovitch, M. (2016). In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation 133, 1783–1794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itasaki, N., Bel-Vialar, S., and Krumlauf, R. (1999). ‘Shocking’ developments in chick embryology: electroporation and in ovo gene expression. Nat Cell Biol 1, E203–E207.

    Article  CAS  PubMed  Google Scholar 

  • Jensen, P., Farago, A.F., Awatramani, R.B., Scott, M.M., Deneris, E.S., and Dymecki, S.M. (2008). Redefining the serotonergic system by genetic lineage. Nat Neurosci 11, 417–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen, K.B., Driskell, R.R., and Watt, F.M. (2010). Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis. Nat Protoc 5, 898–911.

    Article  CAS  PubMed  Google Scholar 

  • Jopling, C., Boue, S., and Izpisua Belmonte, J.C. (2011). Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 12, 79–89.

    Article  CAS  PubMed  Google Scholar 

  • Kim, C.F.B., Jackson, E.L., Woolfenden, A.E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R.T., and Jacks, T. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835.

    Article  CAS  PubMed  Google Scholar 

  • Kretzschmar, K., and Watt, F.M. (2012). Lineage tracing. Cell 148, 33–45.

    Article  CAS  PubMed  Google Scholar 

  • Larijani, B., Esfahani, E.N., Amini, P., Nikbin, B., Alimoghaddam, K., Amiri, S., Malekzadeh, R., Yazdi, N.M., Ghodsi, M., Dowlati, Y., et al. (2012). Stem cell therapy in treatment of different diseases. Acta Med Iran 50, 79–96.

    PubMed  Google Scholar 

  • Lee, C.M., Zhou, L., Liu, J., Shi, J., Geng, Y., Liu, M., Wang, J., Su, X., Barad, N., Wang, J., et al. (2020). Single-cell RNA-seq analysis revealed long-lasting adverse effects of tamoxifen on neurogenesis in prenatal and adult brains. Proc Natl Acad Sci USA 117, 19578–19589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemischka, I.R., Raulet, D.H., and Mulligan, R.C. (1986). Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927.

    Article  CAS  PubMed  Google Scholar 

  • Li, G., Xu, A., Sim, S., Priest, J.R., Tian, X., Khan, T., Quertermous, T., Zhou, B., Tsao, P.S., Quake, S.R., et al. (2016). Transcriptomic profiling maps anatomically patterned subpopulations among single embryonic cardiac cells. Dev Cell 39, 491–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Y., He, L., Huang, X., Bhaloo, S.I., Zhao, H., Zhang, S., Pu, W., Tian, X., Li, Y., Liu, Q., et al. (2018). Genetic lineage tracing of nonmyocyte population by dual recombinases. Circulation 138, 793–805.

    Article  CAS  PubMed  Google Scholar 

  • Li, Y., Lv, Z., He, L., Huang, X., Zhang, S., Zhao, H., Pu, W., Li, Y., Yu, W., Zhang, L., et al. (2019). Genetic tracing identifies early segregation of the cardiomyocyte and nonmyocyte lineages. Circ Res 125, 343–355.

    Article  CAS  PubMed  Google Scholar 

  • Li, Y., Lv, Z., Zhang, S., Wang, Z., He, L., Tang, M., Pu, W., Zhao, H., Zhang, Z., Shi, Q., et al. (2020). Genetic fate mapping of transient cell fate reveals N-cadherin activity and function in tumor metastasis. Dev Cell 54, 593–607.e5.

    Article  CAS  PubMed  Google Scholar 

  • Lin, B., Srikanth, P., Castle, A.C., Nigwekar, S., Malhotra, R., Galloway, J. L., Sykes, D.B., and Rajagopal, J. (2018). Modulating cell fate as a therapeutic strategy. Cell Stem Cell 23, 329–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, E.Y., Jones, J.G., Li, P., Zhu, L., Whitney, K.D., Muller, W.J., and Pollard, J.W. (2003). Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163, 2113–2126.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu, C., Sage, J.C., Miller, M.R., Verhaak, R.G.W., Hippenmeyer, S., Vogel, H., Foreman, O., Bronson, R.T., Nishiyama, A., Luo, L., et al. (2011). Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, K., Yu, W., Tang, M., Tang, J., Liu, X., Liu, Q., Li, Y., He, L., Zhang, L., Evans, S.M., et al. (2018). A dual genetic tracing system identifies diverse and dynamic origins of cardiac valve mesenchyme. Development 145, dev167775.

    Article  PubMed  Google Scholar 

  • Liu, K., Jin, H., and Zhou, B. (2020a). Genetic lineage tracing with multiple DNA recombinases: A user’s guide for conducting more precise cell fate mapping studies. J Biol Chem 295, 6413–6424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, K., Tang, M., Jin, H., Liu, Q., He, L., Zhu, H., Liu, X., Han, X., Li, Y., Zhang, L., et al. (2020b). Triple-cell lineage tracing by a dual reporter on a single allele. J Biol Chem 295, 690–700.

    Article  PubMed  Google Scholar 

  • Liu, K., Tang, M., Liu, Q., Han, X., Jin, H., Zhu, H., Li, Y., He, L., Ji, H., and Zhou, B. (2020c). Bi-directional differentiation of single bronchioalveolar stem cells during lung repair. Cell Discov 6, 1.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu, Q., Yang, R., Huang, X., Zhang, H., He, L., Zhang, L., Tian, X., Nie, Y., Hu, S., Yan, Y., et al. (2016). Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. Cell Res 26, 119–130.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Q., Liu, K., Cui, G., Huang, X., Yao, S., Guo, W., Qin, Z., Li, Y., Yang, R., Pu, W., et al. (2019). Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction. Nat Genet 51, 728–738.

    Article  CAS  PubMed  Google Scholar 

  • Livet, J., Weissman, T.A., Kang, H., Draft, R.W., Lu, J., Bennis, R.A., Sanes, J.R., and Lichtman, J.W. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 56–62.

    Article  CAS  Google Scholar 

  • Madisen, L., Zwingman, T.A., Sunkin, S.M., Oh, S.W., Zariwala, H.A., Gu, H., Ng, L.L., Palmiter, R.D., Hawrylycz, M.J., Jones, A.R., et al. (2010). A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13, 133–140.

    Article  CAS  PubMed  Google Scholar 

  • Madisen, L., Garner, A.R., Shimaoka, D., Chuong, A.S., Klapoetke, N.C., Li, L., van der Bourg, A., Niino, Y., Egolf, L., Monetti, C., et al. (2015). Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metzger, D., Ali, S., Bornert, J.M., and Chambon, P. (1995). Characterization of the amino-terminal transcriptional activation function of the human estrogen receptor in animal and yeast cells. J Biol Chem 270, 9535–9542.

    Article  CAS  PubMed  Google Scholar 

  • Molkentin, J.D. (2014). Letter by molkentin regarding article, “The absence of evidence is not evidence of absence: the pitfalls of Cre knock-ins in the c-Kit locus”. Circ Res 115, e21–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molkentin, J.D., and Houser, S.R. (2013). Are resident c-Kit+ cardiac stem cells really all that are needed to mend a broken heart? Circ Res 113, 1037–1039.

    Article  CAS  PubMed  Google Scholar 

  • Nabhan, A.N., Brownfield, D.G., Harbury, P.B., Krasnow, M.A., and Desai, T.J. (2018). Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 359, 1118–1123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nadal-Ginard, B., Ellison, G.M., and Torella, D. (2014). Absence of evidence is not evidence of absence. Circ Res 115, 415–418.

    Article  CAS  PubMed  Google Scholar 

  • Nagy, A. (2000). Cre recombinase: the universal reagent for genome tailoring. Genesis 26, 99–109.

    Article  CAS  PubMed  Google Scholar 

  • Nieto, M.A., Huang, R.Y.J., Jackson, R.A., and Thiery, J.P. (2016). Emt: 2016. Cell 166, 21–45.

    Article  CAS  PubMed  Google Scholar 

  • O’Rourke, K.P., Loizou, E., Livshits, G., Schatoff, E.M., Baslan, T., Manchado, E., Simon, J., Romesser, P.B., Leach, B., Han, T., et al. (2017). Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat Biotechnol 35, 577–582.

    Article  PubMed  PubMed Central  Google Scholar 

  • Oh, H., Bradfute, S.B., Gallardo, T.D., Nakamura, T., Gaussin, V., Mishina, Y., Pocius, J., Michael, L.H., Behringer, R.R., Garry, D.J., et al. (2003). Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100, 12313–12318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei, W., Feyerabend, T.B., Rössler, J., Wang, X., Postrach, D., Busch, K., Rode, I., Klapproth, K., Dietlein, N., Quedenau, C., et al. (2017). Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfister, O., Oikonomopoulos, A., Sereti, K.I., Sohn, R.L., Cullen, D., Fine, G.C., Mouquet, F., Westerman, K., and Liao, R. (2008). Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells. Circ Res 103, 825–835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plummer, N.W., Evsyukova, I.Y., Robertson, S.D., de Marchena, J., Tucker, C.J., and Jensen, P. (2015). Expanding the power of recombinase-based labeling to uncover cellular diversity. Development 142, 4385–4393.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raven, A., Lu, W.Y., Man, T.Y., Ferreira-Gonzalez, S., O’Duibhir, E., Dwyer, B.J., Thomson, J.P., Meehan, R.R., Bogorad, R., Koteliansky, V., et al. (2017). Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawlins, E.L., Okubo, T., Xue, Y., Brass, D.M., Auten, R.L., Hasegawa, H., Wang, F., and Hogan, B.L.M. (2009). The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodríguez, C.I., Buchholz, F., Galloway, J., Sequerra, R., Kasper, J., Ayala, R., Stewart, A.F., and Dymecki, S.M. (2000). High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat Genet 25, 139–140.

    Article  PubMed  Google Scholar 

  • Rodriguez-Fraticelli, A.E., Wolock, S.L., Weinreb, C.S., Panero, R., Patel, S.H., Jankovic, M., Sun, J., Calogero, R.A., Klein, A.M., and Camargo, F.D. (2018). Clonal analysis of lineage fate in native haematopoiesis. Nature 553, 212–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rompolas, P., Deschene, E.R., Zito, G., Gonzalez, D.G., Saotome, I., Haberman, A.M., and Greco, V. (2012). Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration. Nature 487, 496–499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salwig, I., Spitznagel, B., Vazquez-Armendariz, A.I., Khalooghi, K., Guenther, S., Herold, S., Szibor, M., and Braun, T. (2019). Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo. EMBO J 38.

  • Serakinci, N., Christensen, R., Graakjaer, J., Cairney, C.J., Keith, W.N., Alsner, J., Saretzki, G., and Kolvraa, S. (2007). Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart. Exp Cell Res 313, 1056–1067.

    Article  CAS  PubMed  Google Scholar 

  • Snippert, H.J., van der Flier, L.G., Sato, T., van Es, J.H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A.M., van Rheenen, J., Simons, B.D., et al. (2010). Intestinal Crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144.

    Article  CAS  PubMed  Google Scholar 

  • Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21, 70–71.

    Article  CAS  PubMed  Google Scholar 

  • Sousa, V.H., Miyoshi, G., Hjerling-Leffler, J., Karayannis, T., and Fishell, G. (2009). Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb Cortex 19, i1–i10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Srinivas, S., Watanabe, T., Lin, C.S., William, C.M., Tanabe, Y., Jessell, T. M., and Costantini, F. (2001). Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1, 4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sultana, N., Zhang, L., Yan, J., Chen, J., Cai, W., Razzaque, S., Jeong, D., Sheng, W., Bu, L., Xu, M., et al. (2015). Resident c-kit+ cells in the heart are not cardiac stem cells. Nat Commun 6, 8701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarlow, B.D., Finegold, M.J., and Grompe, M. (2014). Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60, 278–289.

    Article  CAS  PubMed  Google Scholar 

  • Tian, X., Pu, W.T., and Zhou, B. (2015). Cellular origin and developmental program of coronary angiogenesis. Circ Res 116, 515–530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Berlo, J.H., Kanisicak, O., Maillet, M., Vagnozzi, R.J., Karch, J., Lin, S.C.J., Middleton, R.C., Marbán, E., and Molkentin, J.D. (2014). c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viader-Llargués, O., Lupperger, V., Pola-Morell, L., Marr, C., and López-Schier, H. (2018). Live cell-lineage tracing and machine learning reveal patterns of organ regeneration. eLife 7, e30823.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vieugué, P., and Blanpain, C. (2020). Recording EMT activity by lineage tracing during metastasis. Dev Cell 54, 567–569.

    Article  PubMed  Google Scholar 

  • Wagers, A.J., and Weissman, I.L. (2004). Plasticity of adult stem cells. Cell 116, 639–648.

    Article  CAS  PubMed  Google Scholar 

  • Weinreb, C., Rodriguez-Fraticelli, A., Camargo, F.D., and Klein, A.M. (2020). Lineage tracing on transcriptional landscapes links state to fate during differentiation. Science 367, eaaw3381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisblat, D.A., Sawyer, R.T., and Stent, G.S. (1978). Cell lineage analysis by intracellular injection of a tracer enzyme. Science 202, 1295–1298.

    Article  CAS  PubMed  Google Scholar 

  • Xiong, S., Feng, Y., and Cheng, L. (2019). Cellular reprogramming as a therapeutic target in cancer. Trends Cell Biol 29, 623–634.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, M., Shook, N.A., Kanisicak, O., Yamamoto, S., Wosczyna, M. N., Camp, J.R., and Goldhamer, D.J. (2009). A multifunctional reporter mouse line for Cre- and FLP-dependent lineage analysis. Genesis 47, 107–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yanger, K., Zong, Y., Maggs, L.R., Shapira, S.N., Maddipati, R., Aiello, N. M., Thung, S.N., Wells, R.G., Greenbaum, L.E., and Stanger, B.Z. (2013). Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27, 719–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zakrzewski, W., Dobrzyński, M., Szymonowicz, M., and Rybak, Z. (2019). Stem cells: past, present, and future. Stem Cell Res Ther 10, 68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, H., Pu, W., Tian, X., Huang, X., He, L., Liu, Q., Li, Y., Zhang, L., He, L., Liu, K., et al. (2016). Genetic lineage tracing identifies endocardial origin of liver vasculature. Nat Genet 48, 537–543.

    Article  PubMed  Google Scholar 

  • Zhao, H., and Zhou, B. (2019). Dual genetic approaches for deciphering cell fate plasticity in vivo: more than double. Curr Opin Cell Biol 61, 101–109.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000 and XDA16010507), the National Key Research and Development Program of China (2019YFA0110403 and 2019YFA0802000), National Natural Science Foundation of China (31730112, 31625019, 91849202, and 82008810001).

Author information

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Hengwei Jin, Kuo Liu & Bin Zhou

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Bin Zhou

  3. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Kuo Liu & Bin Zhou

Authors
  1. Hengwei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kuo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Zhou.

Ethics declarations

Compliance and ethics The author(s) declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, H., Liu, K. & Zhou, B. Dual recombinases-based genetic lineage tracing for stem cell research with enhanced precision. Sci. China Life Sci. 64, 2060–2072 (2021). https://doi.org/10.1007/s11427-020-1889-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-020-1889-9

Keywords

Search

Navigation