An Introduction to Planarians and Their Stem Cells


Of all animals, it is perhaps planarians that have the greatest ability to regenerate. These once classical classroom organisms have now become the subject of advanced molecular genetic studies that have the potential to inform us about our own biology. Regeneration relies upon a population of pluripotent adult stem cells, called neoblasts. These collectively pluripotent stem cells underpin the regenerative capacity of planarians. The underlying molecular mechanisms controlling their proliferation, self‐renewal and differentiation are now being described. In particular, progress has been made in describing the expression profile of these cells and identifying some of the molecular mechanisms that regulate their behaviour leading to a better understanding of how these cells power regeneration.

Key Concepts

  • Planarians are bilaterians and share many cell and tissue types with other animals including vertebrates.

  • Planarians are able to mount a profound regenerative response to wounding allowing even small fragments to regenerate whole new worms.

  • Planarian regeneration requires the proliferation and differentiation of a population of pluripotent stem cell population called neoblasts.

  • Expression profiling of the neoblast population shows they are a heterogeneous population and express gene regulatory networks in common with both somatic and germline stem cells

  • Many cell biological and molecular genetic approaches can be used to study gene function in planarians allowing novel biological insights to be made, relevant to our own biology.

  • Current research has uncovered many important regulatory processes that regulate stem cells, including those regulated by transcription factors, chromatin modification and RNA binding proteins.

  • Future work will uncover the detailed mechanisms that control stem cell proliferation, self‐renewal and differentiation as well as how missing structures are accurately restored.

Keywords: pluripotency; regeneration; stem cell; progeny; RNA interference; differentiation

Figure 1. (a) Examples of planarians from left to right and . (b) Live imaging of planarian gut structures in purple showing primary, secondary and tertiary anterior and posterior branches using acetyl‐pentafluorobenzene sulphonyl fluorescein (which is converted to its fluorescent form when exposed to H2O2). (c) Monoclonal anti‐3C11 antibody in green shows the nervous system structures cephalic ganglia, ventral nerve cords and transverse fibres. (d) RNA probe for neoblast marker in yellow, nuclear stain DAPI in blue. (e) Monoclonal anti‐H3P antibody labels mitotic cells in green against red autofluorescence. The antibody recognises Histone H3 when phosphorylated at Serine 10 during mitosis. (f) Genes required for neoblast maintenance are often associated with chromatoid bodies. Cells are stained with anti‐tudor antibody labelling the peri‐nuclear CB structures of neoblasts in green and neoblasts are also labelled in red by marker . (g) Anti‐a tubulin in red. The antibody recognizes acetylated tubulin and labels planarian protonephridia cilia as well as dorsal and ventral cilia. Scale bars represent 100 µm for (a)–(e) and (g) and 10 µm for (f).
Figure 2. (a) An overview of selected genes required for the maintenance/self‐renewal and differentiation of two discrete neoblast populations (σ and ζ). Boxed in orange are several genes known to be necessary for neoblast maintenance. is required for the formation of the germline. , , and are not initially required for stem cell maintenance, but are necessary for the proper production of progeny and ultimately for the production of new differentiated tissues as required during regeneration and homeostasis. All these genes are expressed in neoblasts and p53 is also expressed in early post‐mitotic progeny. Boxed in green are a selection of genes that are used as markers of different progenitor types. Each is associated with a specific lineage choice/tissue fate, except the category marker that labels a transitioning progenitor cell based on their expression dynamics after irradiation but are of unknown lineage. (b) Cartoon representation of neoblasts in yellow ( , with their sub‐population (σ and ζ) illustrated with a red and blue outline, respectively. Early progenitors in green ( and late progenitors in purple ( are shown to have different spatial distributions during homeostasis and regeneration. The cells are located within the mesenchyme with cells radiating more peripherally cells expressing the most peripheral expression During regeneration, the spatial distribution of and breaks down and cell types can no longer be compartmentalised. Mitotic σ accumulate at the post‐blastema region, with post‐mitotic cells located with the blastema proper. (c) showing from left to right merged image of distribution during homeostasis, with subsequent single channels labelled. (d) Showing from left to right cells accumulating at the post‐blastema region in a 5‐day regenerate and not within the blastema proper. In green is a separate image of cells located throughout the animal, including within the blastema proper, a distribution mirrored by purple + and highlighted more clearly in the merged image of and + at day 5 of regeneration. Scale bars represent 100 µm for all images.
Figure 3. Lines indicate cell types that express the adjacent gene and the overlapping of lines represents co‐expression overlaps between cell types. Models propose that a large σ neoblast population produces (1) optic cup, (2) protonephridia, (3) serotonergic progenitors and (4) intestinal phagocytes and that the production of these post‐mitotic progeny are all specified from the cycling neoblast population ( and mRNA). Different groups of neoblasts have been shown to co‐express (1) and ( ), (2) and ( ), (3) and ( ), or ( ) and ( ). Progenitors subsequently undergo changes in gene expression that include the loss of neoblast markers ‐, the retention of existing tissue‐specific expression and the additional expression of differentiated markers. SMEDWI protein produced in neoblasts, but persistent in progenitors, has also been used to show lineage‐related differentiation: (1) Optic cup progenitors that are retain expression and additionally express as they are incorporated into the eye. (2) Protonephridia progenitors that become ‐ remain (tubule‐associated cell fate) or (tubule cell fate) and additionally express or respectively. (3) Serotonergic precursors that are ‐ retain and co‐express differentiation marker once differentiated. (4) Finally, intestinal phagocytic precursors that are ‐ retain expression, and co‐express the terminal marker, ceramide synthase.


Aboobaker AA and Kao D (2012) A lack of commitment for over 500 million years: conserved animal stem cell pluripotency. The EMBO Journal 31: 2747–2749.

Adell T, Cebrià F and Saló E (2010) Gradients in planarian regeneration and homeostasis. Cold Spring Harbor Perspectives in Biology 2: a000505–a000505.

Almuedo‐Castillo M, Crespo X, Seebeck F, et al. (2014) JNK controls the onset of mitosis in planarian stem cells and triggers apoptotic cell death required for regeneration and remodeling. PLoS Genetics 10: e1004400.

Bonuccelli L, Rossi L, Lena A, et al. (2010) An RbAp48‐like gene regulates adult stem cells in planarians. Journal of Cell Science 123: 690–698.

Brumbaugh KM, Otterness DM, Geisen C, et al. (2004) The mRNA surveillance protein hSMG‐1 functions in genotoxic stress response pathways in mammalian cells. Molecular Cell 14: 585–598.

Carnevali MDC and Burighel P (2001) Regeneration in Echinoderms and Ascidians, eLS. Chichester, UK: John Wiley & Sons, Ltd.

Currie KW and Pearson BJ (2013) Transcription factors lhx1/5‐1 and pitx are required for the maintenance and regeneration of serotonergic neurons in planarians. Development (Cambridge, England) 140: 3577–3588.

Dinsmore CE (2001) Regeneration: Principles, eLS. John Wiley & Sons, Ltd.

Eisenhoffer GT, Kang H and Sánchez Alvarado A (2008) Molecular analysis of stem cells and their descendants during cell turnover and regeneration in the planarian Schmidtea mediterranea. Cell Stem Cell 3: 327–339.

Forsthoefel DJ, James NP, Escobar DJ, et al. (2012) An RNAi screen reveals intestinal regulators of branching morphogenesis, differentiation, and stem cell proliferation in planarians. Developmental Cell 23: 691–704.

Geyer KK, Chalmers IW, Mackintosh N, et al. (2013) Cytosine methylation is a conserved epigenetic feature found throughout the phylum Platyhelminthes. BMC Genomics 14: 462.

González‐Estévez C, Felix DA, Rodríguez‐Esteban G and Aboobaker AA (2012a) Decreased neoblast progeny and increased cell death during starvation‐induced planarian degrowth. The International Journal of Developmental Biology 56: 83–91.

González‐Estévez C, Felix DA, Smith MD, et al. (2012b) SMG‐1 and mTORC1 act antagonistically to regulate response to injury and growth in planarians. PLoS Genetics 8: e1002619–e1002619.

Guo T, Peters AHFM and Newmark PA (2006) A Bruno‐like gene is required for stem cell maintenance in planarians. Developmental Cell 11: 159–169.

Hayashi T, Shibata N, Okumura R, et al. (2010) Single‐cell gene profiling of planarian stem cells using fluorescent activated cell sorting and its ‘index sorting’ function for stem cell research. Development, Growth & Differentiation 52: 131–144.

Jaber‐Hijazi F, Lo PJ, Mihaylova Y, et al. (2013) Planarian MBD2/3 is required for adult stem cell pluripotency independently of DNA methylation. Development Biology 384: 141–153.

Kandul NP and Noor MAF (2009) Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno‐3. BMC Genetics 10: 67.

Labbé RM, Irimia M, Currie KW, et al. (2012) A comparative transcriptomic analysis reveals conserved features of stem cell pluripotency in planarians and mammals. Stem Cells (Dayton, Ohio) 30: 1734–1745.

Lapan SW and Reddien PW (2011) dlx and sp6‐9 Control optic cup regeneration in a prototypic eye. PLoS Genetics 7: e1002226–e1002226.

Marz M, Seebeck F and Bartscherer K (2013) A Pitx transcription factor controls the establishment and maintenance of the serotonergic lineage in planarians. Development 140: 4499–4509.

Masse I, Molin L, Mouchiroud L, et al. (2008) A novel role for the SMG‐1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. PloS one 3: e3354–e3354.

Onal P, Grün D, Adamidi C, et al. (2012) Gene expression of pluripotency determinants is conserved between mammalian and planarian stem cells. The EMBO Journal 31: 2755–2769.

Oviedo NJ, Pearson BJ, Levin M and Sánchez Alvarado A (2008) Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling. Disease Models & Mechanisms 1: 131–143; discussion 141.

Palakodeti D, Smielewska M, Lu YC, Yeo GW and Graveley BR (2008) The PIWI proteins SMEDWI‐2 and SMEDWI‐3 are required for stem cell function and piRNA expression in planarians. RNA 14: 1174–1186.

Poss KD (2010) Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature Reviews Genetics 11: 710–722.

Reddien PW (2011) Constitutive gene expression and the specification of tissue identity in adult planarian biology. Trends in Genetics: TIG 27: 277–285.

Reddien PW (2013) Specialized progenitors and regeneration. Development (Cambridge, England) 140: 951–957.

Reddien PW, Oviedo NJ, Jennings JR, Jenkin JC and Sánchez Alvarado A (2005) SMEDWI‐2 is a PIWI‐like protein that regulates planarian stem cells. Science (New York, NY) 310: 1327–1330.

Rink JC (2013) Stem cell systems and regeneration in planaria. Development Genes and Evolution 223: 67–84.

Roberts TL, Ho U, Luff J, et al. (2013) Smg1 haploinsufficiency predisposes to tumor formation and inflammation. Proceedings of the National Academy of Sciences of the United States of America 110: E285–E294.

Rouhana L, Vieira AP, Roberts‐Galbraith RH and Newmark PA (2012) PRMT5 and the role of symmetrical dimethylarginine in chromatoid bodies of planarian stem cells. Development (Cambridge, England) 139: 1083–1094.

Saló E (2006) The power of regeneration and the stem‐cell kingdom: freshwater planarians (Platyhelminthes). BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 28: 546–559.

Salvetti A, Rossi L, Lena A, et al. (2005) DjPum, a homologue of Drosophila Pumilio, is essential to planarian stem cell maintenance. Development (Cambridge, England) 132: 1863–1874.

Scimone ML, Meisel J and Reddien PW (2010) The Mi‐2‐like Smed‐CHD4 gene is required for stem cell differentiation in the planarian Schmidtea mediterranea. Development (Cambridge, England) 137: 1231–1241.

Scimone ML, Srivastava M, Bell GW and Reddien PW (2011) A regulatory program for excretory system regeneration in planarians. Development (Cambridge, England) 138: 4387–4398.

Solana J (2013) Closing the circle of germline and stem cells: the Primordial Stem Cell hypothesis. EvoDevo 4: 2.

Solana J, Gamberi C, Mihaylova Y, et al. (2013) The CCR4‐NOT complex mediates deadenylation and degradation of stem cell mRNAs and promotes planarian stem cell differentiation. PLoS Genetics 9: e1004003.

Solana J, Kao D, Mihaylova Y, et al. (2012) Defining the molecular profile of planarian pluripotent stem cells using a combinatorial RNAseq, RNA interference and irradiation approach. Genome Biology 13: R19–R19.

Solana J, Lasko P and Romero R (2009) Spoltud‐1 is a chromatoid body component required for planarian long‐term stem cell self‐renewal. Developmental Biology 328: 410–421.

Tan TC, Rahman R, Jaber‐Hijazi F, et al. (2012) Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms. Proceedings of the National Academy of Sciences of the United States of America 109: 4209–4214.

Wagner DE, Ho JJ and Reddien PW (2012) Genetic regulators of a pluripotent adult stem cell system in planarians identified by RNAi and clonal analysis. Cell Stem Cell 10: 299–311.

Wagner DE, Wang IE and Reddien PW (2011) Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science 332: 811–816.

Wang Y, Zayas RM, Guo T and Newmark PA (2007) Nanos function is essential for development and regeneration of planarian germ cells. Proceedings of the National Academy of Sciences of the United States of America 104 (14): 5901–5906.

Wenemoser D, Lapan SW, Wilkinson AW, Bell GW and Reddien PW (2012) A molecular wound response program associated with regeneration initiation in planarians. Genes & Development 26: 988–1002.

Wenemoser D and Reddien PW (2010) Planarian regeneration involves distinct stem cell responses to wounds and tissue absence. Developmental Biology 344: 979–991.

van Wolfswinkel JC, Daniel EW and Reddien PW (2014) Single‐cell analysis reveals functionally distinct classes within the planarian stem cell compartment. Cell Stem Cell S1934‐5909 (14): 00255‐0. DOI: 10.1016/j.stem.2014.06.007.

Zoran MJ (2001) Regeneration in Annelids, eLS. Chichester, UK: John Wiley & Sons, Ltd.

Further Reading

Aboobaker AA (2011) Planarian stem cells: a simple paradigm for regeneration. Trends in Cell Biology 21 (5): 304–11. DOI: 10.1016/j.tcb.2011.01.005.

Baguñà J (2012) The planarian neoblast: the rambling history of its origin and some current black boxes. The International Journal of Developmental Biology 56 (1–3): 19–37. DOI: 10.1387/ijdb.113463jb.

Elliott SA and Sánchez AA (2013) The history and enduring contributions of planarians to the study of animal regeneration. Wiley Interdisciplinary Reviews: Developmental Biology 2 (3): 301–26. DOI: 10.1002/wdev.82.

Gentile L, Cebrià F and Bartscherer K (2011) The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration. Disease Models & Mechanisms 4 (1): 12–9. DOI: 10.1242/dmm.006692.

Lobo D, Beane WS and Levin M (2012) Modeling planarian regeneration: a primer for reverse‐engineering the worm. PLOS Computational Biology 8 (4): e1002481. DOI: 10.1371/journal.pcbi.1002481.

Tanaka EM and Reddien PW (2011) The cellular basis for animal regeneration. Developmental Cell 21 (1): 172–85. DOI: 10.1016/j.devcel.2011.06.016.

Umesono Y and Agata K (2009) Evolution and regeneration of the planarian central nervous system. Development, Growth and Differentiation 51 (3): 185–95. DOI: 10.1111/j.1440-169X.2009.01099.x.

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Aboukhatwa, Ellen, and Aboobaker, Aziz(Jan 2015) An Introduction to Planarians and Their Stem Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001097.pub2]