Planarian flatworms are famous for their ability to rapidly regenerate new heads or even entire organisms from a tiny fragment of the animal. Planarian regeneration involves a population of proliferative cells (neoblasts) that include pluripotent adult stem cells (cNeoblasts) that can produce every cell of the adult animal. Despite centuries of fascination with regeneration, mechanistic explanations await elucidation. The broad, long-term objectives of this proposal are to use planarians as a model system to identify and understand the molecular mechanisms that regulate stem cells to promote regeneration.
The specific aims are: 1) to determine the functions of neoblast regulatory genes, 2) to identify the cellular basis for regeneration, and 3) to identify wound-induced mechanisms that activate neoblast regenerative responses. Stem cells and regenerative biology are the subjects of recent and intense interest for regenerative medicine. In addition, the misregulation of stem cells may be central to many types of cancer. A newly developed arsenal of tools for molecular genetic study of planarians now exists. For example, systematic gene perturbation with RNA interference (RNAi) is now possible and the planarian genome has been sequenced. Greater than half of planarian genes have counterparts in the human genome;therefore, planarian studies should identify conserved stem cell regulatory genes.
Aim #1 will determine the role of the transcription factor SoxP-1 in regulating gene expression in the neoblasts, utilizing RNAi, flow cytometry, and quantitative mRNA sequencing (RNA-seq). cNeoblasts can produce colonies of descendant cells including neoblasts and differentiating cells spanning germ layers.
Aim #1 will utilize features of cNeoblast colonies to characterize roles for genes with enriched expression in the neoblast population.
Aim #2 will utilize RNA seq and in situ hybridizations to identify the molecular features of the cNeoblast that distinguish it from lineage-committed descendant cells.
Aim #2 will also utilize cNeoblast isolation and transplantation to develop neoblast genetic manipulation tools.
Aim #3 will determine how organ precursors respond to injuries that remove target tissues. Specifically, eyes will be injured partially or completely to investigate whether eye precursors are induced by small eye injuries and in appropriate numbers tailored to the injury type. Finally, the roles of genes induced to be expressed in neoblasts following injury, including two genes encoding conserved Runx-family transcription factors, will be determined using RNAi and cellular assays for neoblast response to wounds. Successful completion of proposed aims will greatly advance our understanding of the mechanistic basis for regeneration and advance planarians as a model system for the study of genes conserved in humans in stem cell and regenerative biology, areas of great importance in human health.
Stem cells are important for public health because they are essential for the growth and maintenance of tissues and lie at the heart of many cancers. Additionally, many regenerative medicine strategies propose the utilization of stem cells to replace missing or undesirable cells. Planarians present a new and powerful system to identify existing molecular mechanisms that regulate stem cells for regeneration.
|Fincher, Christopher T; Wurtzel, Omri; de Hoog, Thom et al. (2018) Cell type transcriptome atlas for the planarian Schmidtea mediterranea. Science 360:|
|Atabay, Kutay Deniz; LoCascio, Samuel A; de Hoog, Thom et al. (2018) Self-organization and progenitor targeting generate stable patterns in planarian regeneration. Science 360:404-409|
|Scimone, M Lucila; Cote, Lauren E; Reddien, Peter W (2017) Orthogonal muscle fibres have different instructive roles in planarian regeneration. Nature 551:623-628|
|LoCascio, Samuel A; Lapan, Sylvain W; Reddien, Peter W (2017) Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration. Dev Cell 40:381-391.e3|
|Oderberg, Isaac M; Li, Dayan J; Scimone, M Lucila et al. (2017) Landmarks in Existing Tissue at Wounds Are Utilized to Generate Pattern in Regenerating Tissue. Curr Biol 27:733-742|
|Wurtzel, Omri; Oderberg, Isaac M; Reddien, Peter W (2017) Planarian Epidermal Stem Cells Respond to Positional Cues to Promote Cell-Type Diversity. Dev Cell 40:491-504.e5|
|Wang, Irving E; Lapan, Sylvain W; Scimone, M Lucila et al. (2016) Hedgehog signaling regulates gene expression in planarian glia. Elife 5:|
|Scimone, M Lucila; Cote, Lauren E; Rogers, Travis et al. (2016) Two FGFRL-Wnt circuits organize the planarian anteroposterior axis. Elife 5:|
|Wurtzel, Omri; Cote, Lauren E; Poirier, Amber et al. (2015) A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians. Dev Cell 35:632-645|
|Owen, Jared H; Wagner, Daniel E; Chen, Chun-Chieh et al. (2015) teashirt is required for head-versus-tail regeneration polarity in planarians. Development 142:1062-72|
Showing the most recent 10 out of 30 publications