Interest in stem cells has seen dramatic growth in the past 20 years. This has been driven, in part, by the significant potential of stem cells in therapeutic applications. In addition, the recently developed in vivo assays allowing cell and lineage tracing and those based on high throughput analyses have provided novel insights on the features of stem cells and their cellular environment. Critical for medical applications is a detailed understanding of the in vivo biology of stem cells, their niches and local signals and their response to the external environment. This knowledge will complement the dissection of their molecular and epigenetic landscapes. Our research program will address the biology of stem cells in vertebrate and invertebrate model systems.
Stem cells are controlled by intrinsic and extrinsic factors
The textbook image of a stem cell is that upon cell division, it produces two daughter cells, one self-renewed stem cell and one daughter cell that undergoes further differentiation. This simplistic view is challenged however from careful analysis of many different stem cell types. This work suggests instead that the ability to self-renew and differentiate is often regulated at the population level, with individual stem cells undergoing symmetric self-renewing, symmetric differentiating, and asymmetric cell divisions. Thus while local, intrinsic stem cell regulation is important, extrinsic factors acting at local and global levels also have essential functions in the coordination of stem cell properties allowing tissue homeostasis. Transcription factors are essential intrinsic factors well described in many models to control stem cell fate and differentiation programs. While many of these factors are defined, a detailed mechanistic understanding of how they coordinate downstream gene regulator networks is still lacking. In addition, an emerging theme in stem cell biology is the importance of stem cell-intrinsic chromatin and epigenetic regulation. Similarly, important intrinsic roles in stem cells and differentiating progenitors of post-transcriptional regulators such as noncoding RNAs (miRNAS, lincRNAs, piRNA) and alternative splicing machinery are beginning to be revealed. Extrinsic regulation of stem cell properties through interactions with niche and environmental signals involves many known signaling pathways such as Notch and Wnt, though their roles are not fully delineated. In addition, signaling in response to the environment including endocrine and metabolic stimuli is poorly defined. Our combined research program will explore how these mechanisms contribute to the coordination of stem cell properties. In particular, we aim to address the following questions:
1. How is stem cell proliferation status (quiescent vs proliferative) controlled?
2. What characterizes niches (microenvironment) and how do they impact the stem cells; how does the external environment (systemic factors) control stem cells?
3. What are mechanisms allowing stem cell specification and cell fate decisions during differentiation?
Stem cells during regeneration
In addition to their important roles in the routine renewal of our tissues, a regenerative response can be mounted upon injury. Regenerative responses may involve similar mechanisms to routine maintenance or may involve distinct types of regulation allowing expansion of the stem cell pool and enhanced differentiation. Importantly, defining and understanding mechanisms employed during regeneration in vivo have important implications for regenerative medicine and the ex vivo expansion of stem cells for therapeutic purposes. In our network through the investigation of regenerative responses in a wide variety of stem cell types and models, we will ask:
4. How does stem cell-mediated regeneration occur and what important factors contribute to this?
Roles of stem cells in pathology
Stem cells are essential to maintain healthy tissues, but can also drive pathologies when they act aberrantly. Aging, for example, is associated with the functional decline of tissues and defects in tissue-specific stem cells. The precise mechanisms causing stem cells to be deregulated during aging are unclear though may be linked, in some instances, to the accumulation DNA mutations. The accumulation of somatic mutations poses a particular risk in stem cells as they are the long-lived resident cells of tissues. In addition to potential roles in stem cell decline during aging, stem cell mutation also leads to cancer. Indeed, stem cells have been demonstrated in many cancers to be the cells of origin through inactivation of tumor suppressor genes or activation of oncogenes. Addressing mechanistically how mutations lead to proliferative advantages of stem or stem-like cells occurs is an important ongoing area of cancer biology. The work of our consortium will contribute important answers to these questions:
5. How is genome stability of stem cells maintained and how do somatic mutations of stem cells contribute to tissue defects? How are stem cells deregulated in pathological contexts?
Stem cells are controlled by intrinsic and extrinsic factors
The textbook image of a stem cell is that upon cell division, it produces two daughter cells, one self-renewed stem cell and one daughter cell that undergoes further differentiation. This simplistic view is challenged however from careful analysis of many different stem cell types. This work suggests instead that the ability to self-renew and differentiate is often regulated at the population level, with individual stem cells undergoing symmetric self-renewing, symmetric differentiating, and asymmetric cell divisions. Thus while local, intrinsic stem cell regulation is important, extrinsic factors acting at local and global levels also have essential functions in the coordination of stem cell properties allowing tissue homeostasis. Transcription factors are essential intrinsic factors well described in many models to control stem cell fate and differentiation programs. While many of these factors are defined, a detailed mechanistic understanding of how they coordinate downstream gene regulator networks is still lacking. In addition, an emerging theme in stem cell biology is the importance of stem cell-intrinsic chromatin and epigenetic regulation. Similarly, important intrinsic roles in stem cells and differentiating progenitors of post-transcriptional regulators such as noncoding RNAs (miRNAS, lincRNAs, piRNA) and alternative splicing machinery are beginning to be revealed. Extrinsic regulation of stem cell properties through interactions with niche and environmental signals involves many known signaling pathways such as Notch and Wnt, though their roles are not fully delineated. In addition, signaling in response to the environment including endocrine and metabolic stimuli is poorly defined. Our combined research program will explore how these mechanisms contribute to the coordination of stem cell properties. In particular, we aim to address the following questions:
1. How is stem cell proliferation status (quiescent vs proliferative) controlled?
2. What characterizes niches (microenvironment) and how do they impact the stem cells; how does the external environment (systemic factors) control stem cells?
3. What are mechanisms allowing stem cell specification and cell fate decisions during differentiation?
Stem cells during regeneration
In addition to their important roles in the routine renewal of our tissues, a regenerative response can be mounted upon injury. Regenerative responses may involve similar mechanisms to routine maintenance or may involve distinct types of regulation allowing expansion of the stem cell pool and enhanced differentiation. Importantly, defining and understanding mechanisms employed during regeneration in vivo have important implications for regenerative medicine and the ex vivo expansion of stem cells for therapeutic purposes. In our network through the investigation of regenerative responses in a wide variety of stem cell types and models, we will ask:
4. How does stem cell-mediated regeneration occur and what important factors contribute to this?
Roles of stem cells in pathology
Stem cells are essential to maintain healthy tissues, but can also drive pathologies when they act aberrantly. Aging, for example, is associated with the functional decline of tissues and defects in tissue-specific stem cells. The precise mechanisms causing stem cells to be deregulated during aging are unclear though may be linked, in some instances, to the accumulation DNA mutations. The accumulation of somatic mutations poses a particular risk in stem cells as they are the long-lived resident cells of tissues. In addition to potential roles in stem cell decline during aging, stem cell mutation also leads to cancer. Indeed, stem cells have been demonstrated in many cancers to be the cells of origin through inactivation of tumor suppressor genes or activation of oncogenes. Addressing mechanistically how mutations lead to proliferative advantages of stem or stem-like cells occurs is an important ongoing area of cancer biology. The work of our consortium will contribute important answers to these questions:
5. How is genome stability of stem cells maintained and how do somatic mutations of stem cells contribute to tissue defects? How are stem cells deregulated in pathological contexts?
