Asymmetric stem cell division oriented by a local self-renewing signal

Funding Type: 
Basic Biology IV
Grant Number: 
Award Value: 
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
Public Abstract: 
When stem cells divide, the two daughter cells have a choice. Commonly, one of the daughter cells becomes a new stem cell while the other one will be more specialized (or differentiated). This property -- the ability to generate more stem cells (self-renewal) while making differentiated cells simultaneously -- defines a stem cell. Stem cells have the unique ability to divide asymmetrically but how this happens is poorly understood. Moreover, there is little knowledge on the mechanisms by which external signals control asymmetric division of stem cells. In tissues, it is also essential that the orientation of stem cell division is properly regulated. At the most fundamental level, asymmetry and the orientation of cell division are at the heart of stem cell biology. We have found that we can instruct stem cells to divide in an asymmetric way by applying an external signaling molecule (called Wnt) to stem cells in a spatially controlled way. We found that the proximal daughter cell will become another stem cell while the distal cell is differentiated. We propose to examine the organization of human stem cells as they divide asymmetrically. Using live imaging microscopy and other tools, we intend to follow how critical determinants segregate over the two daughter cells. We expect that the new mechanistic insights into asymmetric stem cell division will ultimately lead to a better understanding of the possible use of stem cells for therapy.
Statement of Benefit to California: 
This research proposal aims at understanding asymmetric divisions of stem cells, a fundamental biological property. The research will initially increase our insights into the basic biology of stem cells. In the longer term however, this work will also lead to better methods to manipulate stem cells for therapeutic purposes, as it will be essential to understand the ways that stem cells divide and differentiate. Our work will also lead to technological advances that will be of use to stem cell researchers and stem cell-based applications. In fact, we have already made several advances in designing methods to direct the growth of stem cells, including the use of artificial niches and the use of specific growth factors that influence stem cells.
Progress Report: 
By dividing asymmetrically, stem cells maintain their numbers and to generate differentiated daughter cells. In this work, we aim to answer fundamental questions on the regulation and mechanisms of asymmetric stem cell division. We address In particular how asymmetric stem cell division is influenced by external signals, such as those provided by stem cell niches. Using asymmetric exposure of single stem cells to a Wnt protein, we have discovered that the Wnt signal governs both stem cell fate and orientation of division simultaneously. We are now extending this work to include human stem cells, those of epidermal origin and embryonic stem cells. We have designed experiments to elucidate the mechanism of asymmetric stem cell division.