Periodic Reporting for period 1 - i-SignalTrace (Deciphering signalling pathway dynamics during cell-fate commitment in stem cells)
Période du rapport: 2023-03-01 au 2025-08-31
Like us, cells are continuously exposed to chemicals, nutrients, and contact with other cells (among other stimuli), which help them shape their identity. Also like us, the impact of such stimuli is not always the same: depending on their identity, cells might react differently to the same chemical. Also like for most of us, cellular identity (also referred to as cellular state) is not a static concept and can change during the course of life. With this in mind, several questions arise: do different cells in the same state react differently to the same stimulus? Can we predict how the same cell will react differently to the same stimulus at different times of its life? Does a cell remember the sequence of stimuli it has been exposed? Does such memories impact cell identity?
Being able to answer these questions would allow to anticipate the most likely trajectory that a cell will follow when subject to external perturbations and decipher the role of cellular heterogeneity. With this, we will become better at (re-)programming cell identity in vitro, which can give rise to novel and efficient personalised therapies for some diseases. Hence, the acquired knowledge will impact both fundamental developmental biology and translational regenerative medicine, which will benefit a much wider scientific community.
Within i-SignalTrace, our goal is to establish the experimental and analytical tools to investigate how cells react to stimuli at a particular time in their lives, and how this reaction impacts their identity (and the identity of their offspring) later.
Hence, we aim to establish molecular machines to "write" how different perturbations affect the expression of a some key genes. This information will be recorded in the cellular DNA forever, and will even be transferred to the daughter cells. By sequencing, we will then be able to "read" it and quantify the gene history of each cell and based on the stimuli it underwent.
Being able to answer these questions would allow to anticipate the most likely trajectory that a cell will follow when subject to external perturbations and decipher the role of cellular heterogeneity. With this, we will become better at (re-)programming cell identity in vitro, which can give rise to novel and efficient personalised therapies for some diseases. Hence, the acquired knowledge will impact both fundamental developmental biology and translational regenerative medicine, which will benefit a much wider scientific community.
Within i-SignalTrace, our goal is to establish the experimental and analytical tools to investigate how cells react to stimuli at a particular time in their lives, and how this reaction impacts their identity (and the identity of their offspring) later.
Hence, we aim to establish molecular machines to "write" how different perturbations affect the expression of a some key genes. This information will be recorded in the cellular DNA forever, and will even be transferred to the daughter cells. By sequencing, we will then be able to "read" it and quantify the gene history of each cell and based on the stimuli it underwent.
Our machines are based the success of Cas9-based genome editing technologies in human stem cells.
For that, we simultaneously screened over several Cas9-based proteins as well as editing target sites to select the most efficient candidates in stem cells.
Remarkably, we managed also to design a molecular machine that we can switch on an off at will, giving us the power to decide when to record cellular's behaviour. In addition, this allows us to listen more than once during the lifetime of the cell and funnel down how a sequence of reactions to the same perturbation can shape different cell identities.
Since stem cells are crucial during early development, in parallel we established in the lab differentiation protocols that push stem cells out of pluripotency towards different progenitors that present in our bodies when we are embryos. Within i-SignalTrace, we aim to reconstruct the decision landscape of stem cells during such an important time of our lives. Nevertheless, our tools will easily be transferred to investigate how cells behave in scenarios that better recapitulate our adult bodies.
For that, we simultaneously screened over several Cas9-based proteins as well as editing target sites to select the most efficient candidates in stem cells.
Remarkably, we managed also to design a molecular machine that we can switch on an off at will, giving us the power to decide when to record cellular's behaviour. In addition, this allows us to listen more than once during the lifetime of the cell and funnel down how a sequence of reactions to the same perturbation can shape different cell identities.
Since stem cells are crucial during early development, in parallel we established in the lab differentiation protocols that push stem cells out of pluripotency towards different progenitors that present in our bodies when we are embryos. Within i-SignalTrace, we aim to reconstruct the decision landscape of stem cells during such an important time of our lives. Nevertheless, our tools will easily be transferred to investigate how cells behave in scenarios that better recapitulate our adult bodies.
One of the drives in regenerative medicine is to (re-)program cells from patients for disease modelling, drug screening, and transplantation therapies.
Conclusions within i-SignalTrace we will based on data obtained using a single pluripotent stem cell line derived from a donor. Nevertheless, the response to perturbations might depend also on the cell background, questioning the universality of our results. Do my cells respond equal than yours to the same chemical? Therefore, once i-SignalTrace establishes the framework to predict how a stem cells react to stimuli, it will be crucial to investigate how translational our results are to other cell lines. Our vision is that eventually we will identify key donor-specific markers that will make our predictions more general. Those markers might be patient-specific mutations, small differences in gene expression, or epigenomic diferences. Furhter research, hence, will have to be performed in the effect of the epigenome, and whether memory plays a role, in cell-fate response to stimuli.
Conclusions within i-SignalTrace we will based on data obtained using a single pluripotent stem cell line derived from a donor. Nevertheless, the response to perturbations might depend also on the cell background, questioning the universality of our results. Do my cells respond equal than yours to the same chemical? Therefore, once i-SignalTrace establishes the framework to predict how a stem cells react to stimuli, it will be crucial to investigate how translational our results are to other cell lines. Our vision is that eventually we will identify key donor-specific markers that will make our predictions more general. Those markers might be patient-specific mutations, small differences in gene expression, or epigenomic diferences. Furhter research, hence, will have to be performed in the effect of the epigenome, and whether memory plays a role, in cell-fate response to stimuli.