Mechanisms of regeneration and stem cell control
Our laboratory studies how complex tissues and organs regenerate under normal conditions and in response to injury or disease. We aim to understand:
1. The nature of stem cell regulatory networks
Homeostasis of many organs largely depends on the activities of tissue-specific stem cells. In the past, a lot of research has been focused on understanding how individual stem cells respond to signals from their micro-environment and decide between remaining quiescent and becoming activated. However, it was unclear if and how thousands of stem cells can coordinate their activities with one another.
Recently, we were able to study collective behavior of adult stem cells using the model of hair regeneration. Each hair has a prominent cluster of stem cells. Since there are thousands of hairs on the surface of the skin and skin is flat, together all hair stem cells form a two-dimensional network of clusters. Within this network each stem cell cluster “listens” to competing activating and inhibitory signals and decides between remaining quiescent and becoming activated based on the combined signaling message that it receives. Because the decision making rules are similar for every stem cell cluster, scaling of this behavior across the entire network results in striking patterns of hair regeneration.
To this end, we developed a mathematical approach that enables predictive modeling of the hair regeneration patterns. Using predictive power of the model, we showed how key BMP and WNT signaling pathways from the stem cell micro-environment become reused to mediate long-range communication between neighboring hair stem cell clusters. Currently we are interested in the following questions:
A) In addition to WNT and BMP, what other key signaling pathways are co-opted to regulate large-scale regeneration of hair stem cells? We are using the predictive computational modeling coupled with in vivo validation experiments to identify new players in the hair stem cell signaling network.
B) Does large-scale coordination exist among stem cells in tissues other than skin? We are looking to identify the analogous two- and three-dimensional stem cell networks in other organs.
C) Can stem cell coordination be modulated to design more physiologically-relevant stem cell-based therapies?
2. Regenerative behavior in response to organ injury
Our laboratory is also interested to understand the natural limits of adult cells’ plasticity in response to injury. Our ongoing work shows that the regenerative abilities of adult mammalian skin are far greater than previously thought. In the center of large skin wounds cells can acquire an embryonic-like state and develop new, fully functioning hair follicles. New adipose tissue regenerates around these hair follicles. Recently we showed that new adipocytes regenerate from myofibroblasts, scar-forming cells thought to be non-adipogenic. Myofibroblasts convert to adipocytes via the process of lineage reprogramming. Such reprogramming is triggered by hair-derived BMP signals, that activate adipocyte-specific transcription factors. Collectively, regenerative events can be so efficient that several months after wounding, scar tissue can hardly be distinguished from the normal skin. Using this regeneration model, we are studying:
A) What mechanism allows lineage-restricted adult cells to expand their developmental plasticity in response to wounding?
B) How can embryonic-like regeneration be enhanced to achieve scarless healing of adult tissues?