Society for Investigative Dermatology (SID) Annual Meeting, Atlanta, USA, May, 2015
2015 (74th) Society for Investigative Dermatology (SID) Annual Meeting, Atlanta, USA, May 6-9, 2015,
695, Rapid hair cycle pattern breakdown during mouse development revealed with the aid of mathematical modeling
J Oh, Q Wang, Q Nie and M Plikus
University of California, Irvine, Irvine, CA
Recognized for its periodicity, excitability, and patterning, the hair follicle (HF) is becoming a preferred biological system for the mathematical modeling of regeneration. Cyclic growth of HFs is regulated both by signaling interactions within the HF (signaling micro-environment) and long-range signals between neighboring HFs and other skin cells (macro-environment). Herein, we developed a mathematical model based on the molecular dynamics of parallel activator/inhibitor pathways, where both single HF and population level behaviors emerge naturally upon scaling. We modeled the phenomenon of age-dependent hair cycle pattern breakdown, wherein highly synchronous hair growth in the first two cycles is thought to become replaced by the asymmetric hair growth waves in the third cycle. Surprisingly, our modeling shows that the breakdown in the hair growth symmetry requires approximately ten hair cycles, far more than the observable two cycles. Additional simulations predicted two new requirements for the rapid hair growth pattern evolution: (i) hair growth asynchrony must already exist during the first, morphogenetic hair cycle; and (ii) two or more HF populations with distinct hair cycle parameters must interact with one another. Next, we performed a detailed hair growth pattern analysis during the first two hair cycles. Indeed, we found previously unrecognized spatial-temporal wave of hair morphogenesis. Furthermore, we identified previously unknown interactions between anatomically distinct HF populations at the onset of the second anagen. Taken together, here we applied a Systems Biology approach to reveal previously unrecognized hair cycle dynamics that contribute to rapid hair growth pattern evolution in mouse skin. Our findings challenge the prevailing view that the first two hair cycles as been synchronous. They have important implications for designing and interpreting future hair cycle experiments.
Google Scholar [Link]
JID [Link]
Google Scholar [Link]
JID [Link]
Program book [Link]
693, Studying hair cycle clock with the aid of multi-scale diffusion-based mathematical modeling
J Oh, Q Wang, Q Nie and M Plikus
University of California, Irvine, Irvine, CA
Hair follicle (HF) is the model system of choice for studying mechanisms of regeneration. Each HF features a prominent stem cell compartment and a tractable regeneration cycle, consisting of the anagen, catagen, and telogen phases. To-date, the fundamental mechanism underlying the timing of hair growth, aka “hair cycle clock” remains largely unknown. One possibility is that the hair cycle clock is composed of two or more activator and inhibitor signaling pathway pairs and that key hair cycle phase transitions occur at certain cumulative thresholds for these pathway activities. Herein we developed a mathematical model that accounts for natural HF geometry and cell dynamics. Incorporating activator/inhibitor signals in the context of this model produces stable periodicity and excitability – hallmark features of the natural hair cycle. In the context of our model, activator/inhibitor signals were predicted to have opposing effects on anagen and telogen phase periodicity. Increasing activator levels was predicted to shorten telogen and lengthen anagen. The inverse effects were modeled for an inhibitor. Here, we focused on anagen phase length and validated these predictions for BMP/WNT signaling pair. Using mouse models we show that decreasing inhibitory BMP signaling leads to the production of longer hairs, thus indicating a longer anagen. We also demonstrate that decreasing activating WNT signaling in mutant mice results in shorter hairs. Finally, we showed that some hair types were the most sensitive to changes in BMP levels than others, suggesting differential effects of BMP modulation. Simulations of this phenomenon suggests that changes in just one background model parameter is sufficient to recapitulate differential sensitivity of hair types to the same net change in the activator/inhibitor signaling levels. Taken together, we provide the first example of a diffusion-based mathematical model that accounts for realistic changes in HF geometry, displays stable periodicity and excitability. It creates a novel opportunity for studying the hair cycle clock mechanism using Systems Biology approach.
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JID [Link]
Program book [Link]
Second Joint Symposium of Young Basic Medical Scientists
2nd Joint Symposium of Young Basic Medical Scientists, Daegu, Korea, Aug 29, 2014,
“The dynamics of skin patterns in terms of hair follicle excitations” (Invited)
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Society for Investigative Dermatology (SID) Annual Meeting, Albuquerque, USA, May 7-10, 2014
2014 (73rd) Society for Investigative Dermatology (SID) Annual Meeting,
Albuquerque, USA, May 7-10, 2014,
"Hair cycles of Transplanted Human Hairs in Immunocompromised mice"
276
274
Albuquerque, USA, May 7-10, 2014,
"Hair cycles of Transplanted Human Hairs in Immunocompromised mice"
J Oh, M Kim, M Plikus, J Kim
JOURNAL OF INVESTIGATIVE DERMATOLOGY 134, S47-S47
276
Hair cycles of transplanted human hairs in immunocompromised mice
J Oh,1,2 M Kim,2 M Plikus1 and J Kim2 1 Developmental and Cell Biology, University of California, Irvine, Irvine, CA and 2 Department of Immunology and Hair Research Center, Kyungpook National University School of Medicine, Daegu, Republic of Korea
Growth of human scalp hair follicles is characterized by short telogen and prolonged anagen, often lasting many years. This makes it difficult to reliably capture the event of telogen-to-anagen transition. Because anagen initiation is a clinically relevant event in the human hair growth cycle, there is an unmet need for a better experimental model. In this study we aimed to characterize temporal dynamics of human scalp hair follicle regeneration in human-on mouse xenotransplantation model. We transplanted human scalp follicles into the skin of immuno-compromised nude (Foxn1 null) and SCID mice and carefully analyzed temporal dynamics of post-transplantation telogen-to-anagen transitions on serial-section histology and immunohistochemistry. Hair follicles were analyzed for up to one year after xenotransplantation, initially with 7-day intervals. Based on our histological studies and mathematical analysis we were able to construct a detailed probabilistic timeline of post-transplantation hair cycle phases. We distinguished the following phases: transplantation-induced catagen stages I, II, III, transitional stage (aka new anagen initiation), anagen II, III, IV, V, VI. Probabilistically, the peak in transitional stage hair follicles occured on post-transplantations day 33 in SCID mice and day 37 in nude mice. Our results provide a detailed experimental blueprint for future studies tasked with studying signaling regulation of human anagen initiation in human-on-mouse xenotransplantation model. Importantly, they also reveal that the choice of host (nude vs. SCID mouse) as an important experimental parameter to consider.
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Journal of Investigative dermatology [Link]
"Regulation of ear morphogenesis by macroenvironmental signals from hair follicles"
R Ramos, T Hsi, J Oh, CF Guerrero-juarez, M Plikus
JOURNAL OF INVESTIGATIVE DERMATOLOGY 134, S47-S47
274
Regulation of ear morphogenesis by macroenvironmental signals from hair follicles
R Ramos, T Hsi, J Oh, CF Guerrero-juarez and M Plikus Developmental and Cell Biology, University of California, Irvine, Irvine, CA
Hair follicle (HF) regeneration involves not only intrinsic signals from different HF compartments, but also inputs coming from the extra-follicular macroenvironment. Such signals can come from neighboring HFs, adipocytes, pre-adipocytes, and possibly other tissue-resident skin cells, allowing for collective regenerative behavior. We posit that skin also provides an ideal model to study the macroenvironmental regulation of morphogenesis. In the mouse external ear, a 2-3 cell-thick sheet of chondrocytes located in the center, comes in direct contact with HFs of the ear skin on both sides. We show that in mouse ear, development of HFs and cartilage closely overlaps in time and in space, providing a novel model to study signaling crosstalk between their respective morphogenetic programs. In the HF, WNT signaling acts to promote early morphogenesis and cyclic regeneration. In the cartilage, WNTs have been implicated in chondroblast proliferation and chondrocyte differentiation. Here, we evaluated the possibility of WNT signaling crosstalk in the shared ear skin / cartilage macroenvironment by modulating WNT signaling outputs using transgenic approaches. We first analyzed the effects of epithelial WNT overexpression on cartilage morphogenesis. Because ear shape and size are directly proportional to cartilage cell number, ear morphology can be used as a sensitive rheostat of chondrocyte population size. Mice overexpressing epithelial Wnts have significantly larger ears compared to WT control; consistent with the known function of WNT in delaying the onset of terminal chondrocyte differentiation. However, in a mouse model expressing soluble WNT antagonist in skin epithelia, ears become misshapen and notably elongated, but, surprisingly, not smaller. These results suggest that ear HFs and cartilage morphogenesis occur in shared signaling macroenvironment and reveal HF-derived WNT signaling inputs as functionally important modulators of auricular chondrogenesis.
