The extracellular matrix (ECM) does not only provide with a physical or structural support to cells and tissues but also it is a source of signaling and regulatory functions that impact most biological functions. Consequently, regeneration is also a process in which the ECM may obviously play an important role. Thus, for instance, just think on freshwater planarians. During regeneration and homeostasis stem cells proliferate and migrate towards the tissues or structures in which new cells are needed (i.e. the blastema or an old organ). Also, during these processes, the planarians may go through an extensive remodeling of the preexisting tissues. Considering the relevance that the ECM appears to have in regulating cell adhesion, cell migration and stem cell niche, self-renewal or differentiation in other systems, it is surprising how little we know about the role of ECM during planarian regeneration, or even how it changes during the required remodeling associated to regeneration or homeostasis. Now, a recent paper by Isolani and collaborators from the laboratory of Renata Batistoni reports the functional characterization of four matrix metalloproteinases (MMPs) in these animals (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055649).
Surprisingly, the silencing of two of these MMPs (mmp1, a zinc-dependent proteinase and mt-mmpA, a membrane-anchored proteinase) results in very severe (leading to lethality) phenotypes affecting normal homeostasis in intact planarians, but without apparently impairing regeneration in a significant way. This is true especially for mmp-1, whereas the knockdown of mt-mmpA delays the normal growth and differentiation of the blastema. The silencing of mmp-1 in non-regenerating animals results in tissue disorganization, breaking of the basal lamina and multilayered epidermis. At the cellular level, and compared to controls, the number of proliferating neoblasts appear to increase at 2-3 days of RNAI but then it goes down to the same level as in controls, whereas there is an increase in the expression of post-mitotic markers. On the other hand there is a significant decrease in apoptotic cell death which the authors interpret as mmp-1 being a positive regulator of apoptosis in planarians. In the case of mt-mmpA its silencing in intact non-regenerating animals also leads them to die. However, here, neoblast proliferation is not affected at any time-point, the expression of post-mitotic markers is reduced and authophagy is significantly increased. From BrdU labeling the authors conclude that mt-mmpA may mediate cell migration during homeostasis.
Further experiments are required to better characterize how the silencing of these MMPs alters the ECM as well as any ECM-cell interaction to explain the severe phenotypes observed. It will be also important to determine which cell types (neoblasts or differentiated cells or both) are involved and why these defects do not appear during regeneration. Still, this work may represent a stimulating starting point to characterize the function of ECM during planarian regeneration and homeostasis.