Adult Stem Cells Have Memory

Why Previously Injured Skin Heals Faster Than Normal

Tissues in our body contain small niches of quiescent adult stem cells that can, upon demand, multiply and differentiate into myriad somatic cell types as required and dictated by environmental demands. In the skin, stem cells can divide and transform into cell types that produce, for example, collagens, pigment, and keratin. Stem cells in the skin also create a secretome that includes signaling molecules and matrix proteins, used for many purposes including to help build the skin’s thick extracellular matrix. Serving as cellular factories for other cell types and a vast array of secreted molecules, the multiple stem cell types in the skin now appear to have another function as recently demonstrated in a collaboration between the laboratories of Dr. Shruti Naik, Ph.D. and Dr. Elaine Fuchs, Ph.D., both of whom are professors at The Rockefeller University (Naik et al, 2017).  Drs. Naik and Fuchs showed that if patches of skin in mice were wounded, causing inflammation, then allowed to heal, subsequent wounds in the same patch of skin would heal about 2.5 times more quickly than adjacent, previously unwounded skin. The effect in previously wounded skin could last up to six months given the conditions of the experiment. This functional adaptation was attributed to epithelial stem cells (EpSCs) and did not require an immune response because skin-resident macrophages and T cells were not involved. What the study showed was that EpSCs maintain chromosomal accessibility, where the DNA is less tightly packed and open to signals from the damaged tissue, at key stress response genes, activated by the inflammatory stimulus. This epigenetic change in the chromatin allowed, during a secondary inflammtory challenge to the same skin patch, genes in that patch of skin to be transcribed rapidly. While the secretome of skin stem cells has previously been shown to be altered by wounding, the exact nature of changes in the secretome was not reported in this study. However, underlying the memory of the stem cells in this study is Aim2, a portion of DNA that encodes an activator of the inflammasome, a conglomerate of proteins that contributes to the skin’s defence against bacteria and viruses. Although having the stem cells remember a wounding event so that future wounds may be more easily healed, like many things in biology where there can be positive effects coupled with potential negative consequences, the epigenetic memory in stem cells may lead to negative cellular behavior, namely overproliferation.  Tumors have often been described as wounds that do not heal.  As Dr. Mina Bissell, Ph.D. at UC Berkeley has taught us, normal tissue homeostasis and architecture inhibit progression of cancer, whereas changes in the microenvironment, such as continuous wounding, can shift the balance of these signals to the procancerous state (Bissell and Hines, 2011). Thus, the constant wounding may change the microenvironment in such a way as to epigenetically shift the stem cells into a very procancerous state, something they remember for a long period of time. An emerging area of research is quickly expanding as scientists continue to explore stem cell memory, and the field of immune-stem cell interactions, and stem cells as a part of the immune system. More about that later.

References

Bissell MJ and Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nature Medicine,17:320-329.

Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550:475–480