Stem cells have a distinct metabolism, and recent advances suggest that key pathways controlling cellular metabolism can also modulate stem cell function. Despite the intensive research in this field, it is not clear if cellular metabolism is a facilitator for other cellular programs orchestrating stem cell fate decisions, or whether certain metabolic features themselves are critical for the establishment and maintenance of stemness. The possibilities of stem cell-based therapies in targeting, for example, aging associated diseases or diabetes, may therefore impinge on the understanding of stem cell metabolism. We combine our expertise on stem cell technologies, nutrient sensing, and on mitochondrial biology to address how integral cellular metabolism is to stem cell identity and function.
Stem Cell Metabolism and Aging
Stem cells maintain our tissues by producing cells for tissue function through differentiation, and new stem cells through self-renewal. By carefully balancing these two possible outcomes among the progeny cells, a single stem cell can in principle provide an endless supply of cells. However, while stem cells of young tissues can maintain tissue function despite constant wear and tear, old stem cells fail to do so. The resulting decline manifests as aging. We aim to reactivate aged stem cells using metabolic cues, and study the possibility to maintain tissue function despite the age-associated accumulation damage. Such strategies could provide health benefits for the aging population by reducing aging associated diseases, and by promoting recovery from accidents or therapies with adverse side effects. We study the intrinsic and extrinsic factors modulating stem cell activity, and focus in understanding how cellular metabolism can influence stem cell identity and function.
First, stem cells match tissue renewal with the availability of resources, and therefore require information on the state of the tissue and organismal physiology. Intriguingly, some stem cells do not directly sense the nutritional state, but rely on messages from their neighbours for that information. This opens the possibility to target such inter-cellular signalling, and to regulate tissue renewal by mimicking the nutritional cues that guide stem cell activity. Second, in order to fulfil their long-term tissue maintaining task, stem cells must divide. We focus in elucidating the role of metabolism in determining the identity of the progeny cells immediately after cell division, and whether certain metabolic tools could be used to guide stem cell self-renewal and differentiation. Such tools could open possibilities to promote tissue regeneration or function depending on the current needs.
Mitochondrial Proteostasis and Stem Cells
Mitochondria are organelles with a central role in cellular metabolism. Several metabolic pathways either occur inside mitochondria or are influenced by mitochondrial function. Mitochondria require more than 1500 proteins for their multiple tasks, and maintenance of a healthy and balanced set of proteins or “proteome” inside mitochondria is critical for optimal functionality. Loss of such protein homeostasis, or “proteostasis”, is harmful for cells, and may contribute to aging. We are interested in the interplay between mitochondrial proteostasis and cellular metabolism, and how these processes affect stem cell maintenance and differentiation.
Mitochondrial function is especially critical in those tissues with high energetic demands such as the skeletal muscle, heart or the brain. Thus, dysfunctional mitochondria cause diseases, which commonly manifest as neuromuscular pathologies. In our studies, we use mouse models that have mutations in genes involved in mitochondrial protein synthesis and import, and we investigate the consequences of these defects in different tissues and stem cells. We also use induced pluripotent stem cells that have been reprogrammed from human patients’ skin cells, and can be differentiated into various cell types such as cardiomyocytes and neurons. We have first studied the genetics of these patients and identified that they carry disease mutations in genes that affect mitochondrial proteostasis. By utilizing genome editing to generate other mutant cell lines we are able to address more specific questions of the role of certain mitochondrial proteins in cellular metabolism and stem cell function. We hope to create models that can be used to address how mitochondrial proteostasis mechanisms modify cellular metabolism, influence stem cell function, and cause mitochondrial disease.
Nutrient Sensing and Stem Cells
Nutrient availability and the capacity of an animal to sense nutrients, such as sugar, is closely coupled to many aspects of physiology including tissue growth, energy homeostasis and aging. We aim to elucidate signaling and gene regulatory mechanisms, which allow tissues to adapt their metabolism in response to changing nutrient content and to communicate with other tissue types to maintain organismal homeostasis. Also tissue stem cells are responsive to nutrition. The intestinal epithelial lining digests and absorbs nutrients from food as well as protects from health threatening substances and pathogens. Homeostasis in the intestine is particularly dependent on the intestinal stem cells. Feeding triggers intestinal stem cells to proliferate, which allows dynamic control of intestinal size. On the other hand, failure in stem cell-mediated intestinal renewal leads to loss of intestinal integrity upon aging. Considering the emerging evidence on metabolic control of stem cell function, it will be important to elucidate how stem cells maintain the proper metabolic status upon conditions of changing nutrient intake.
We focus on the molecular mechanisms that control intestinal stem cell identity and proliferation in response to specific nutrients. Our main model system is the fruit fly Drosophila, which allows us to utilize highly controlled diet manipulations in combination with powerful genetic tools to study the effect of nutrition on stem cell function and animal physiology across many tissues. Our approach utilizes genomics, metabolomics and automated imaging to identify novel regulators of nutrient sensing that will be tested for conservation in mammalian systems. Understanding the mechanisms by which nutrients affect tissue stem cells can lead to safe and feasible interventions to promote human healthspan.
On the fruit fly intestinal stem cell project we also collaborate with MetaStem affiliated PI Jaakko Mattila, who has recently set up his independent research group at the University of Helsinki.
Pluripotent Stem Cells and Diabetes
Pluripotent stem cells are primitive stem cells that can self-renew and differentiate into all embryonic tissues during development. Induced pluripotent stem cells (iPSCs) can be derived in the laboratory by reprogramming adult skin or blood cells. Also iPSCs have the capacity to differentiate into most cell types, making them a valuable resource for disease modeling, drug development, and regenerative therapy. We have developed novel CRISPRa-based tools which allow us to effectively reprogram the fate of cells by activating multiple endogenous genes simultaneously. Using these tools, we aim to understand the mechanisms of very early human embryo development and establish new types of primitive, so called naïve, stem cells. We focus on the metabolic behavior of these stem cells and aim to clarify if universal metabolic switches can be used for more effective reprogramming.
Using patient-derived disease-model iPS cells we can address the mechanisms linking human mutations to pathological state and identify drugs that are effective for the specific disease. For example, beta-cells derived from patient iPS cells make it possible to model human diabetes and study the pathogenetic mechanisms of various forms of monogenic and polygenic diabetes in order to identify specific treatments. iPS cells can further be used for production of functional tissue cells in large quantities for regeneration therapy, such as insulin producing beta cells for the treatment of diabetes. However, iPS-derived beta cells remain metabolically immature and are not able to secrete insulin efficiently in response to elevated glucose levels. We aim to characterize the functional and metabolic maturation of the stem cell derived beta cells in order to achieve fully functional insulin-secreting cells which can be produced in unlimited numbers.
Stem Cell Size and Metabolism
Despite the essential role of stem cells, it is still unclear how they fail to maintain their functions during ageing and disease. We discovered a new aspect of stem cell ageing in vivo: cellular enlargement. Blood stem cells constantly replenish the body’s blood cells and are among the smallest cells in the body. We found that aging and damage drives blood stem cell enlargement, which causes the loss of their functionality. Restoring their small size was sufficient to reinstate functionality, showing that small size is critical for stem cell function. However, we are only beginning to understand how size impacts stem cell fitness and its potential effects on metabolism and physiology.
Our research program utilizes blood (hematopoietic) stem cells (HSCs), which uniquely enables the analysis of stem cell function in vivo. HSCs also play a fundamental role in the ageing of the blood system, ageing-related diseases like leukaemia, and provide a great system to perform clinical research. We study how the novel aging factor - stem cell enragement - drives dysfunction using HSCs of mouse models and human bone marrow donations to identify molecular mechanisms impairing fitness of large stem cells from a metabolic perspective. Furthermore, we are interested in how size-dependent metabolic alterations in stem cells affect tissue decline and diseases like leukemia. Our novel approaches are anticipated to significantly enrich current models as they add a new paradigm to stem cell ageing and metabolism, provide transformative treatment tools, and examine cancer from a new dimension.