What enables some organisms, but not others, to regenerate lost body parts? The answer to this question has profound implications for the field of regenerative medicine, which seeks to understand and harness regenerative mechanisms for repairing or replacing damaged human tissues. The problem of regeneration has challenged scientists ever since Abraham Trembley's experiments on freshwater Hydra launched the era of experimental biology more than 260 years ago; nonetheless, the mechanisms involved in regenerative processes remain poorly understood.
Our model for studying the molecular mechanisms underlying metazoan regeneration is the planarian flatworm, a subject of classic regeneration experiments. The choice of planarians as a system to study the problem of regeneration was based on their remarkable developmental plasticity, the rapidity of their regenerative response, the ease with which they can be cultured in the laboratory, and the stem cell population that gives rise to their regenerative abilities. The development of functional genomic tools for studying the planarian Schmidtea mediterranea has revitalized studies of these fascinating organisms and permits detailed analyses of the mechanisms underlying regeneration.
After a planarian has been transected, the wounded area is rapidly covered by a thin layer of epidermal cells. Stem cells called neoblasts are then signaled to proliferate beneath the wound epithelium, giving rise to an unpigmented structure referred to as the regeneration blastema. As regeneration proceeds, neoblasts continue to accumulate within the blastema, causing it to grow exponentially. Within one week of transection, differentiation of the missing structures occurs. In uninjured planaria, neoblasts are distributed throughout the parenchyma (mesenchyme) and, as the only mitotic somatic cells in the animal, serve as the source of replacement cells during tissue renewal.
Research in my laboratory utilizes the tools of molecular cell biology and functional genomics to address several major biological problems for which planarians serve as excellent models.
Differentiation of the Regenerative Stem Cells: Roles in Regeneration and Tissue Maintenance
How are stem cells specified to adopt specific fates? How is their differentiation choreographed to correctly replace the missing structures? How are newly differentiated cells integrated into functional tissues and organs, during regenerative and homeostatic processes? We are addressing these and related questions by combining high-throughput in situ hybridization and monoclonal antibody screens to identify cell type–specific markers, with microarray analyses and functional studies using double-stranded RNA-mediated genetic interference (RNAi). Our recent work has identified genes required for proper regeneration of the intestine and has revealed a role for an intestinally expressed transcription factor in regulating neoblast proliferation, suggesting that the intestine may serve as a niche regulating neoblast behavior.
Regulation of Germ Cell Development and Differentiation
We are also interested in understanding the mechanisms by which germ cells are specified, and how physiological/environmental signals regulate their proper differentiation. In contrast to the commonly studied genetic model invertebrates, in which localized determinants specify germ cells in the early embryo, planarians use inductive signals to form their germ cells from the somatic stem cells much later in development. Thus, the functional genomic resources available for studying planarians can be used to examine inductive germ cell specification and the factors required to convert a somatic stem cell into a germ cell. We are currently using unbiased, genome-wide approaches to identify both intrinsic and extrinsic factors required for proper germ cell development. We have shown that neuro-endocrine signaling is required for proper development and maintenance of the planarian reproductive organs, identifying a neuropeptide Y superfamily member that mediates this neuronal control of reproductive maturation and maintenance.
Using Planarians as Models for Understanding Parasitic Flatworms
Schistosomes are parasitic flatworms and are the causative agents of schistosomiasis, a major neglected tropical disease affecting hundreds of millions of people. Although parasitic flatworms display several striking differences in their life cycles relative to their free-living relatives, they also share many common features. We are capitalizing on the experimental accessibility of planarians to help us understand several fundamental aspects of schistosome biology. We expect that characterizing shared flatworm-specific mechanisms that regulate organismal survival and reproductive system function will lead to new strategies for targeting these devastating parasites.
This work has also been funded by the National Institutes of Health and the National Science Foundation.
As of March 11, 2016