Project Summary
The capacity to regulate stem and progenitor cells for regeneration is widespread in the animal kingdom and
has attracted investigation for centuries. Evolution has selected for mechanisms involved in wound repair and
tissue regrowth that are the dreams of regenerative medicine. Uncovering the principles of regeneration in
case study organisms should identify processes that naturally promote or limit regeneration, enabling future
development of therapeutic approaches to tissue damage repair. Planarians are flatworms capable of
regenerating any missing body part, including new heads. Their regenerative powers have combined with ease
of experimentation to make them a classic regeneration model. Planarian regeneration involves adult stem
cells called neoblasts, which we previously showed can display pluripotency at the single cell level
(cNeoblasts). A major direction of our research addresses how fate specification occurs in regeneration.
Extensive work indicates that fate choices are made within the neoblasts (called specialized neoblasts), with
the regeneration outgrowth at the wound (a blastema) being a composite of different fate-specified cells. This
highlights the step of fate-choice in neoblast stem cells as central for understanding the mechanistic basis for
planarian regeneration. We seek to understand "specificity" in regeneration, in which diverse injuries appear to
result in responses tailored to the identity of missing tissue. We aim to distinguish between the possible
existence of surveillance systems indicating the presence or absence of differentiated cell types and what we
named target-blind regeneration. In target-blind regeneration, progenitor production occurs at a low basal rate
sufficient for repair from small wounds, without needing tissue surveillance; we hypothesize tissue-specific
progenitor production is primarily regulated by wound-induced proliferation combined with positional
information. We aim to understand how positional information regulates stem cell fate choice during tissue
turnover, and dynamically during regeneration. Our prior work on a planarian whole-animal cell-type
transcriptome atlas indicates the existence of over 100 adult cell types. We seek to understand what processes
within neoblast stem cells regulate how they make any one of so many possible choices. We will study the
pattern of fate choices using spatial transcriptomics and seek to distinguish between a highly regulated fate-
specification process, such as by extrinsic local tissue cues, and a more stochastic process internal to the stem
cells. Finally, we will investigate how adult progenitors generated from stem cells bring about the restoration of
tissue architecture in regeneration. Our prior work indicates that migratory targeting by extrinsic cues combines
with self-organization of progenitors with their target tissue to generate and maintain tissue pattern in
regeneration. We will study the molecular bases for these processes, which will be critical to elucidate for
understanding the basis for tissue repair and regeneration.