Regeneration: The Development of Rebuilding
The use of an adult population of pluripotent stem cells to fuel planarian regeneration presents several important questions. Is this population heterogeneous, or is it derived from a single pluripotent population, as clonal studies (see Figure 22.18) suggest is possible? Moreover, what is the process whereby a neoblast can create the 30 or so cell types of the adult planarian? When does cell specification take place? Could it be that lineage-restricted multipotent stem cells are derived from a cNeoblast and are seeded throughout the flatworm prior to any injury? Or are differentiated postmitotic cells produced directly from a pluripotent neoblast at the time of injury (Figure 1)?
Genetic studies are beginning to unravel some of the answers. The gene smedwi-1 is expressed by all neoblasts and has become the most common marker for their identification across planarian species (Reddien et al. 2005; Reddien 2013). Several studies have revealed that some neoblasts express different sets of transcription factors that correlate with specific cell fates in the planarian adult, which suggests that lineage specification of stem cell populations may exist in the organism for normal development and in response to injury (Hayashi et al. 2010; Pearson et al. 2010; Shibata et al. 2012). To further investigate this possibility, the Reddien lab performed transcriptomic analysis of individual neoblasts during homeostasis and regeneration (van Wolfswinkel et al. 2014). Through this comprehensive analysis, the researchers found that two distinct populations of neoblasts exist, which they named zeta and sigma (Figure 2A). Although zeta and sigma neoblasts are morphologically indistinguishable, they have several defining characteristics: they express different gene regulatory networks, and zeta neoblasts are postmitotic, whereas sigma neoblasts are highly proliferative and are the only stem cells directly responsive to injury. Upon amputation, sigma neoblasts (soxP2-expressing) generate a huge variety of cell types (brain, intestine, muscle, excretory, pharynx, and eyes), as well as the progenitor population for zeta neoblasts. Zeta neoblasts (zfp-1-expressing) are then directly responsible for creating the remaining epidermal cell types. Planarians lacking a zeta population can be made through zfp-1 RNAi knockdown. When the heads of these planarians were amputated, the sigma neoblasts were able to fuel the regeneration of all the cells of new heads, except for the epidermal lineages (Figure 2B and C; van Wolfswinkel et al. 2014). These data all support a vital role for stem cells in regeneration. But we are still left with the question, How are the specific cell types patterned correctly? How does the flatworm tell the posterior blastema to become tail and the anterior blastema to become head?
Literature Cited
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Pearson, B. J. and Sánchez Alvarado, A. 2010. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages. Development 137: 213–221.
Reddien, P. W. 2013. Specialized progenitors and regeneration. Development 140: 951–957.
Reddien, P. W., N. J. Oviedo, J. R. Jennings, J. C. Jenkin and A. Sánchez Alvarado. 2005. SMEDWI-2 is a PIWI-like protein that regulates planarian stem cells. Science 310: 1327–1330.
Shibata, N. and 11 others. 2012. Comprehensive gene expression analyses in pluripotent stem cells of a planarian, Dugesia japonica. Int. J. Dev. Biol. 56: 93–102.
van Wolfswinkel, J. C., D. E. Wager and P. W. Reddien. 2014. Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment. Cell Stem Cell 15: 326–339.