A bioinformatic approach to study context-specific signaling by the stem cell receptor Kit
A major challenge facing all stem cell therapies is regulating the behavior of stem cells – their survival, proliferation, self-renewal and differentiation – to regenerate the desired cell types and tissues. The success of these therapies depends on understanding how extracellular signals, such as growth factors, present in the stem cell niche regulate stem cell behavior through the activation of cell surface receptors.
The receptor Kit is present on the surface of multiple human stem cell types, both pluripotent (embryonic and induced pluripotent) and adult (hematopoietic, cardiac and neural) as well as certain mature cell types. In addition, Kit is required for the maintenance of these cells. Our work will address the following question: how does a receptor that is expressed in stem and non-stem cells, function specifically in the context of stem cells to regulate self-renewal and survival?
We hypothesize Kit achieves context-specific functioning by interacting with and activating other cell surface receptors, each of which is specific to a different stem cell type. Our previous work, combining bioinformatics predictions with experimental validation, has already identified IL-4R as a novel Kit-activated receptor in hematopoietic stem cells. Our proposed research will first extend this work to find similar Kit-activated receptors in the other stem cell types.
To understand the significance of the above Kit-activated receptors, we will compare normal stem cells to those lacking one of these receptors and evaluate the contribution of Kit as well as each Kit-activated receptor to stem cell function. Our final objective is to study the role of microRNAs, a class of small RNA molecules, in the mechanisms by which Kit activation elicits changes in stem cell behavior. A rapidly growing body of evidence suggests that microRNAs play key roles in regulating cellular differentiation but their role in stem cell biology remains unclear.
The research outlined in this proposal is aimed at uncovering a novel paradigm for context-specific activity of the pan-stem cell receptor Kit in multiple human stem cell types. In addition to investigating the mechanisms underlying Kit activity, our work may suggest new stem cell-targeted therapies using combinations of growth factors, that exploit the potential synergy between Kit and the Kit-activated receptors.
The goal of this proposal is to investigate novel mechanisms of action of the stem cell receptor Kit, which is present on embryonic and multiple tissue-specific adult stem cells and known to play a central role in regulating survival, proliferation and self-renewal. Our research is likely to both advance our knowledge of mechanisms underlying stem cell biology and motivate the development of novel stem cell-targeted therapies.
The natural environment of stem cells within different tissues in the body provide a variety of cues in the form of growth factors to promote the survival and self-renewal of stem cells and, when needed, their proliferation and differentiation into various types of mature cells. The successful clinical use of human stem cells requires the ability to maintain and grow these cells, and to stimulate them to develop into the desired tissues. This requires a thorough understanding of the mechanisms by which stem cells respond to extracellular cues, which is the focus of our current and proposed work. We seek to uncover novel interactions between Kit and other stem cell receptors and determine the role of these interactions in regulating stem cell behavior. Our scientific method based on combining bioinformatics with experimental validation, has proven to be much faster than conventional approaches, having accelerated by several years our finding of a novel interaction between Kit and the IL-4 receptor in bone marrow stem cells.
Our results are likely to inform novel stem cell-targeted therapies. Currently, administration of Kit ligand, also known as Stem Cell Factor, at doses necessary to stimulate bone marrow stem cells results in severe adverse effects due to the action of Kit on certain non-stem cells. Our findings on interactions between Kit and other stem cell receptors may provide a basis for combination therapies that utilize much lower doses of Kit ligand together with other growth factors to specifically target the desired stem cells while diminishing the adverse effects.