Scientists identify genes capable of regulating stem cell function

Sep 17, 2008

Scientists from The Forsyth Institute, Boston, MA, and the Howard Hughes Medical Institute at the University of Utah School of Medicine have developed a new system in which to study known mammalian adult stem cell disorders. This research, conducted with the flatworm planaria, highlights the genetic similarity between these invertebrates and mammals in the mechanisms by which stem cell regulatory pathways are used during adult tissue maintenance and regeneration. It is expected that this work may help scientists pursue pharmacological, genetic, and physiological approaches to develop potential therapeutic targets that could repair or prevent abnormal stem cell growth which can lead to cancer.

In recent years, planarians have been recognized as a powerful model system in which to molecularly dissect conserved stem cell regulatory mechanisms in vivo. This research reveals that planaria are also a great model in which to study the molecular relationship between stem cells and cancer. The gene characterized in this study (PTEN) is one of the most commonly mutated genes in human cancers. As in human beings, genetic disturbance of the gene in planarians led to mis-regulation of cell proliferation resulting in cancer-like characteristics. These results indicate that some of the pattern control mechanisms that enable regeneration of complex structures may go awry in cancer.

Abnormal stem cell proliferation in planarians is induced by genetic manipulation of conserved cellular signaling pathways. These abnormal cells can be specifically targeted without disturbing normal stem cell functions that support adult tissue homeostasis and regeneration. Importantly, this type of analysis could not be achieved in more traditional adult invertebrate model systems such as the fruit fly Drosophila and the nematode C. elegans. This research will be published in the journal Disease Models & Mechanisms available online on August 30. According to the paper's lead author, Dr. Néstor J. Oviedo, an Assistant Research Investigator in the Forsyth Center for Regenerative and Developmental Biology, this work provides new opportunities to expand knowledge of this regulatory molecule and the role it plays in cancer and tissue regeneration. "Our findings demonstrate that important signaling pathways regulating adult stem cell proliferation, migration and differentiation are evolutionarily and functionally conserved between planarians and mammals. Planarians are poised to not only advance the understanding of how diverse adult tissues are functionally maintained in vivo, but also will enhance our capabilities to identify, prevent, and remediate abnormal stem cell proliferation."
Summary of Study

The scientists have identified two genes, Smed-PTEN-1 and Smed-PTEN-2, capable of regulating stem cell function in the planarian Schmidtea mediterranea. Both genes encode proteins homologous to the mammalian tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Inactivation of Smed-PTEN-1and -2 by RNA interference (RNAi) in planarians disrupts regeneration, and leads to abnormal outgrowths in both cut and uncut animals followed soon after by death (lysis). The resulting phenotype is characterized by hyperproliferation of neoblasts (planarian stem cells), tissue disorganization and a significant accumulation of postmitotic cells with impaired differentiation capacity. Further analyses revealed that rapamycin selectively prevented such accumulation without affecting the normal neoblast proliferation associated with physiological turnover and regeneration. In animals in which PTEN function is abrogated, the HHMI/University of Utah and Forsyth researchers also detected a significant increase in the number of cells expressing the planarian Akt gene homolog (Smed-Akt). However, functional abrogation of Smed-Akt in Smed-PTENRNAi-treated animals does not prevent cell overproliferation and lethality, indicating that functional abrogation of Smed-PTEN is sufficient to induce abnormal outgrowths. Altogether, the data reveal roles for PTEN in the regulation of planarian stem cells that are strikingly conserved to mammalian models. In addition, the results implicate this protein in the control of stem cell maintenance during the regeneration of complex structures in planarians.

The PTEN molecules were originally identified and characterized in the laboratory of Dr. Alejandro Sanchez Alvarado, HHMI investigator and Professor of Neurobiology and Anatomy at the University of Utah School of Medicine. Dr. Sánchez Alvarado's is the paper's senior author. His laboratory is engaged in the identification of the molecular and cellular basis of animal regeneration. His laboratory's work on planarians has led to the establishment of this organism as an important model system to study stem cells, regeneration and tissue homeostasis.

The Forsyth research team is led by Michael Levin, Ph.D., Senior Member of the Staff in The Forsyth Institute and the Director of the Forsyth Center for Regenerative and Developmental Biology. Through experimental approaches and mathematical modeling, Dr. Levin and his group examine the processes governing large-scale pattern formation and biological information storage during animal embryogenesis. The lab investigates mechanisms of signaling between cells and tissues that allow a living system to reliably generate and maintain a complex morphology. The Levin team studies these processes in the context of embryonic development and regeneration, with a particular focus on the biophysics of cell behavior.

Source: Forsyth Institute

Explore further: Bulletproof nuclei? Stem cells exhibit unusual absorption property

add to favorites email to friend print save as pdf

Related Stories

Growing a business, from the lab

Feb 03, 2014

In the early 1990s, MIT researcher Shuguang Zhang, then an MIT postdoc, stumbled upon peptides that could self-assemble into nanostructures, creating three-dimensional environments for cell culturing. It ...

New mechanism for genome unpacking in stem cells

Jan 27, 2014

Scientists at Karolinska Institutet and Gurdon Institute in Cambridge, United Kingdom have identified a novel mechanism that allows pluripotent stem cells to maintain their genome in an unpacked state, and thereby maintain ...

Recommended for you

Plants with dormant seeds give rise to more species

Apr 18, 2014

Seeds that sprout as soon as they're planted may be good news for a garden. But wild plants need to be more careful. In the wild, a plant whose seeds sprouted at the first warm spell or rainy day would risk disaster. More ...

Researchers successfully clone adult human stem cells

Apr 18, 2014

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

User comments : 0

More news stories

Biologists help solve fungi mysteries

(Phys.org) —A new genetic analysis revealing the previously unknown biodiversity and distribution of thousands of fungi in North America might also reveal a previously underappreciated contributor to climate ...

Making graphene in your kitchen

Graphene has been touted as a wonder material—the world's thinnest substance, but super-strong. Now scientists say it is so easy to make you could produce some in your kitchen.

Growing app industry has developers racing to keep up

Smartphone application developers say they are challenged by the glut of apps as well as the need to update their software to keep up with evolving phone technology, making creative pricing strategies essential to finding ...