Stem cells hold great potential to help us in repairing injured body parts or replacing damaged organs. In order to realize this potential the rules that control stem cell behavior need to be understood. Our laboratory has found that repression of the tumor suppressor p16 in human mammary epithelial cells (HMECs) endows them with specific properties that are only found in classical stem cells and tumor cells. Indeed, repression of p16INK4a in HMECs enables them to grow in culture for a long time, something that HMECs expressing p16INK4a cannot achieve. Importantly, we have previously shown that repression of p16INK4a is accompanied by the acquisition of pre-malignant features.
Thanks to the support of this CIRM grant, we have now established that a sub-population of these cells display stem cell properties. This means that these cells can self-renew but also differentiate in different breast cell types. Unexpectedly, these cells can also give rise to non-breast cells, such as brain cells, when grown in the appropriate cell culture conditions, making this unique cell model a powerful tool for cancer AND regenerative medicine research. Knowing that these cells can generate cells of different tissue types, we can now dissect the rules that dictate those different cell fates. We are also testing whether these exciting findings obtained in cell culture dishes (in vitro) can be confirmed in a mouse model (in vivo). In other words, can these cells generate a functional mammary gland? Other studies, beyond the scope of this application could also test whether these cells could rescue spinal injury.
So why do we bother using breast cells to generate brain cells (or other types of cells)? The answer is that we believe that the sub-population of cells we have identified in breast likely exists as a stem cell pool in any tissue (with some tissue-specific variations of course). If this hypothesis is confirmed, these cells could turn out to represent a major advancement in regenerative medicine. Another major advantage of these naturally occurring stem cells, compared to the widely used embryonic stem cell lines, is that they are directly isolated from fresh breast tissue without introducing artifacts that may result from establishment in long-term cell culture systems. Their properties are an accurate reflection of a fully functional stem cell pool actually existing physiologically in our body.
Understanding how stem cells code their decisions and whether cell fate can be changed after it has been set is key to the effective use of stem cells for therapeutic purposes. Gaining such insights will greatly improve our ability to manage wound repair and organ replacement. This should also help us characterize fundamental switches that control stem cells as well as control the formation of cancer cells since some of the genes that control stem cell properties are mutated in cancer. A mechanistic understanding of how these switches work may help us prevent adverse events that may result from the use of stem cells during regenerative medicine. Thus, we hope to contribute in improving the health of the citizens of California.