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Understanding Stem Cells During Nervous System Development and Repair

Research Summary

Freda Miller is interested in the development and establishment of neural connectivity and in understanding how this is perturbed in pathological situations. She also studies the role stem cells play in the biology of developing and adult tissues, with a particular focus on the central nervous system and the dermis.

During embryonic development, the mammalian nervous system is confronted with a task of enormous complexity: to progress from a thin sheet of neuroepithelial stem cells to a network of neuronal connectivity that is able to process sensory information and generate an appropriate motor output. One way the nervous system achieves this end point is to overproduce neurons and neuronal connections and then eliminate the cells and connections that are not appropriate, a process that is not limited to the developing nervous system. Many of the same cellular mechanisms remain available in adult animals, allowing structural and functional remodeling in response to physiological stimuli and providing repair mechanisms for the injured or degenerating mature nervous system.

These complex developmental processes are determined by an intimate interplay between intrinsic cellular programs and environmental cues. Within this broad context, my laboratory is interested in understanding how the neural environment (1) regulates the genesis of neural cell types from embryonic neural stem cells and (2) determines neuronal survival, growth, and ultimately connectivity. In addition, we hope that the lessons we learn from studying normal neural development can teach us how perturbations in these normal processes lead to cognitive dysfunction and potentially could provide us with strategies for repairing damage from nervous system diseases and injury. With regard to the latter possibility, one approach we have taken is to identify and characterize stem cells that have neural potential, with a particular focus on a novel population of adult dermal stem cells.

Adult stem cells have attracted considerable interest because of their therapeutic potential and the insights they provide about the normal biology of adult mammalian tissues. We previously identified, isolated, and characterized SKPs (skin-derived precursors), a population of multipotent adult stem cells that first appear in the dermis of rodents and humans during embryogenesis and persist into adulthood within a hair follicle niche. Our work indicates that these endogenous SKPs act as a stem cell reservoir for maintenance and repair of the dermis and for regulation of hair follicle morphogenesis. Moreover, we showed that when removed from their dermal environment, SKPs have neural crest–like properties, generating functional mesenchymal and peripheral neural progeny. We are studying endogenous SKPs as a model adult stem cell system, asking about the signals that regulate stem cell–mediated tissue repair and that ensure stem cell longevity for the mammalian life span. Moreover, from a therapeutic perspective, we are identifying compounds that will allow us to recruit endogenous SKPs to enhance tissue repair and regeneration and are pursuing cell-based transplantation approaches, taking advantage of human SKPs as an accessible, potentially autologous human stem cell source.

Our interest in nervous system development and repair has also led us to ask how the environment regulates the development of neural stem cells in the embryonic brain. As one approach to this question, we have asked whether genetic mutations that are causally associated with human cognitive disorders might mediate their effects in part by deregulating developing neural precursors and, by corollary, whether these genes might therefore provide novel insights into pathways that are important for neural precursor biology. Over the past five years, this has turned out to be a fruitful approach for defining important neural precursor pathways and has led to the conclusion that genetically defined perturbations in the timing and numbers of different neural cell types generated during embryogenesis have a profound impact on later developmental events such as neural circuit formation and cognitive function. As a second approach, we have started to ask whether genes that regulate stem cell development in model organisms might also regulate neural precursor development in mammals. We hope that these two approaches will provide us with unbiased insights into neural stem cell biology and with new ways to think about cognitive disorders.

A long-standing interest in the laboratory is how growth factors, particularly neurotrophins, regulate the survival and connectivity of developing neurons. During development, neurons are overproduced; then, neurons that do not make appropriate connections are lost during a period of naturally occurring cell death. Similarly, connections are overproduced, and only some of these are selected for maintenance, while the others are lost during a period of axon pruning. Our work has defined how the neurotrophins, their receptors, and their downstream signaling pathways regulate these losses. This work has taught us that both neuronal death and axon degeneration are active processes and has identified several key intracellular regulators of these events, such as the p53 family members p73 and p63. We are continuing to ask about the biology of axon degeneration in the intact nervous system and about the importance of these same pathways and proteins during central nervous system injury and degeneration.

As of September 26, 2012

Scientist Profile

Senior International Research Scholar
The Hospital for Sick Children
Developmental Biology, Neuroscience