Our lab studies how the cells of the immune system are formed from blood stem cells.
Stem and progenitor cells make ‘decisions’ in order to generate our various tissues and organs. Without these decisions, we would be undifferentiated blobs without eyes and ears, livers and hearts, skin and bone.
To discover the steps of how a stem cell divides and ultimately turns into an organ, we utilise new technologies that interrogate the individual cells, rather than the population as a whole. This is akin to understanding the role of each player in a football team – not only the team’s result.
Our ultimate goal is to advance strategies for manipulating blood stem cells that may have future applications for stem cell therapy or immune therapy, and provide insights into cancer formation.
Cellular barcoding is a technology that allows the tracking of fate for hundreds of single stem cells simultaneously. Each progenitor is tagged with a unique DNA ‘stamp’ such that it is inherited by daughter cells and detected in progeny using DNA sequencing and computational analysis. In this way, we can compare barcode inheritance between cell types to infer their derivation from common vs. separate ancestors. We have used the technique to decipher the complexity of their individual fate and to reconstruct single cell lineage decisions in haematopoiesis (Naik, Nature, 2013).
We are now covering other aspects of haematopoiesis, including how these patterns change upon duress such as infection, and how modification of genetic regulators affects the output of single cells.
Team members: Dawn Lin, Jaring Schreuder
While cellular barcoding can determine the fate of many single cells in vivo, it cannot provide information on the shape of the ‘family tree’ where a single stem cell generates multiple cell types. In order to decipher this tree, one must track the entire process, including division and differentiation, and without loss of identity of individual cells.
To achieve this, we image microwells containing hematopoietic progenitors every 1-2 minutes for five days. In this system we can identify the acquisition of particular fates by cells by including fluorescently-labeled antibodies in the culture medium.
Team member: Dawn Lin
We have previously established that haematopoietic progenitors with very similar phenotypes often exhibit highly heterogeneous fates. Through clone-splitting experiments, where the fates of siblings from a single cell are assessed independently (for example, in two separate wells in vitro or transferred to two recipients in vivo), we have determined that this heterogeneous fate is often ‘imprinted’ (Naik et al. Nature. 2013).
We are tackling the nature of these molecular programs by performing high throughput single cell RNA sequencing – a relatively new but powerful technique – that can reveal single cell resolution differences that may account for differences in fate.
Team member: Jessica Tran
Our team work independently as well as in groups across the different projects.
We work closely with the Hodgkin laboratory (Immunology Division), the Schumacher laboratory (Netherlands Cancer Institute), the Cohen laboratory (Drexel) and the Duffy laboratory (Hamilton Institute).
We seek driven scientists who are open to new technologies and thinking about biology at the single cell level.