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• W2894486342 abstract "•Neighboring epidermal stem cells actively balance their fates over time•Stem cell division is triggered by demand for differentiated cells•Differentiation drives division by neighbor cell enlargement followed by S/G2 entry•Both forced and natural epidermal stem cell loss drive cell divisions Maintenance of adult tissues depends on sustained activity of resident stem cell populations, but the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead, it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation. Maintenance of adult tissues depends on sustained activity of resident stem cell populations, but the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead, it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation. Maintenance of adult tissues depends on sustained activity of resident stem cell populations (Morrison and Spradling, 2008Morrison S.J. Spradling A.C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life.Cell. 2008; 132: 598-611Abstract Full Text Full Text PDF PubMed Scopus (1470) Google Scholar, Simons and Clevers, 2011Simons B.D. Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues.Cell. 2011; 145: 851-862Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). An essential property of these stem cells is their ability to self-renew to preserve the size of the stem cell pool over time. However, the cellular mechanisms that regulate this homeostatic self-renewal remain poorly understood. It remains generally unclear how stem cell self-renewal is regulated in the context of continual cell turnover (e.g., differentiation, cell death, etc.) to buffer against excess or insufficient cell divisions, such as in cancer or degenerative diseases, respectively. Work with epithelial tissues ranging from cultured cells to the developing mouse and zebrafish epidermis suggests that proliferation drives the delamination of nearby cells through a density-dependent mechanism (Eisenhoffer et al., 2012Eisenhoffer G.T. Loftus P.D. Yoshigi M. Otsuna H. Chien C.B. Morcos P.A. Rosenblatt J. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia.Nature. 2012; 484: 546-549Crossref PubMed Scopus (511) Google Scholar, Marinari et al., 2012Marinari E. Mehonic A. Curran S. Gale J. Duke T. Baum B. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding.Nature. 2012; 484: 542-545Crossref PubMed Scopus (289) Google Scholar, Miroshnikova et al., 2018Miroshnikova Y.A. Le H.Q. Schneider D. Thalheim T. Rübsam M. Bremicker N. Polleux J. Kamprad N. Tarantola M. Wang I. et al.Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification.Nat. Cell Biol. 2018; 20: 69-80Crossref PubMed Scopus (135) Google Scholar). This coordination of behaviors is thought to maintain stem cell numbers and local density over time, allowing constitutive stem cell divisions to be compensated by the later exit of neighboring cells via delamination. We do not know whether this relationship between self-renewal and differentiation also occurs in fully developed adult tissues. The ability to investigate this question depends on the tracking of co-existing stem cells as they execute both differentiation and self-renewal behaviors. However, to date, this type of simultaneous, high-resolution spatiotemporal mapping of stem cell fates has not been possible in live adult mammals. The mouse skin epithelium offers a well-studied regenerative system in which to investigate the regulation of stem cell fates. Epidermal stem cells reside in an underlying basal layer, where they either self-renew within this compartment or differentiate by delaminating upward to contribute to the watertight barrier of the skin (Gonzales and Fuchs, 2017Gonzales K.A.U. Fuchs E. Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche.Dev. Cell. 2017; 43: 387-401Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, Simpson et al., 2011Simpson C.L. Patel D.M. Green K.J. Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis.Nat. Rev. Mol. Cell Biol. 2011; 12: 565-580Crossref PubMed Scopus (315) Google Scholar, Solanas and Benitah, 2013Solanas G. Benitah S.A. Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding niche.Nat. Rev. Mol. Cell Biol. 2013; 14: 737-748Crossref PubMed Scopus (107) Google Scholar). Existing strategies to study these cell events have relied on clonal lineage tracing, which has provided fundamental insights into the self-renewal potential of epidermal stem cells but has not addressed the factors that control self-renewal (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar, Doupé et al., 2010Doupé D.P. Klein A.M. Simons B.D. Jones P.H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate.Dev. Cell. 2010; 18: 317-323Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Lim et al., 2013Lim X. Tan S.H. Koh W.L.C. Chau R.M.W. Yan K.S. Kuo C.J. van Amerongen R. Klein A.M. Nusse R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science. 2013; 342: 1226-1230Crossref PubMed Scopus (247) Google Scholar, Mascré et al., 2012Mascré G. Dekoninck S. Drogat B. Youssef K.K. Broheé S. Sotiropoulou P.A. Simons B.D. Blanpain C. Distinct contribution of stem and progenitor cells to epidermal maintenance.Nature. 2012; 489: 257-262Crossref PubMed Scopus (396) Google Scholar, Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar, Roy et al., 2016Roy E. Neufeld Z. Cerone L. Wong H.Y. Hodgson S. Livet J. Khosrotehrani K. Bimodal behaviour of interfollicular epidermal progenitors regulated by hair follicle position and cycling.EMBO J. 2016; 35: 2658-2670Crossref PubMed Scopus (31) Google Scholar, Sada et al., 2016Sada A. Jacob F. Leung E. Wang S. White B.S. Shalloway D. Tumbar T. Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin.Nat. Cell Biol. 2016; 18: 619-631Crossref PubMed Scopus (113) Google Scholar, Sánchez-Danés et al., 2016Sánchez-Danés A. Hannezo E. Larsimont J.C. Liagre M. Youssef K.K. Simons B.D. Blanpain C. Defining the clonal dynamics leading to mouse skin tumour initiation.Nature. 2016; 536: 298-303Crossref PubMed Scopus (70) Google Scholar). Collectively, these studies have shown that epidermal stem cells are equipotent, meaning they are equally capable to undergo self-renewal or terminal differentiation (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar, Doupé et al., 2010Doupé D.P. Klein A.M. Simons B.D. Jones P.H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate.Dev. Cell. 2010; 18: 317-323Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Lim et al., 2013Lim X. Tan S.H. Koh W.L.C. Chau R.M.W. Yan K.S. Kuo C.J. van Amerongen R. Klein A.M. Nusse R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science. 2013; 342: 1226-1230Crossref PubMed Scopus (247) Google Scholar, Mascré et al., 2012Mascré G. Dekoninck S. Drogat B. Youssef K.K. Broheé S. Sotiropoulou P.A. Simons B.D. Blanpain C. Distinct contribution of stem and progenitor cells to epidermal maintenance.Nature. 2012; 489: 257-262Crossref PubMed Scopus (396) Google Scholar, Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar). Despite these advances in delineating stem cell potential, we still fail to understand the physiological cues of self-renewal in the context of other fate decisions taking place in neighboring stem cells as well as how these cues ensure a precise balance of stem cell activity. Here we sought to directly interrogate epidermal stem cell self-renewal in relation to other cell fate decisions taking place in the surrounding tissue. We used an innovative imaging approach to map the timing and location of all self-renewal and differentiation events taking place in large epidermal regions. By combining spatiotemporal mapping of cell fates with newly developed statistical analyses, we find that cell fate choices are locally coordinated, with a lag time of 1 to 2 days. Surprisingly, and in contrast to the developing epidermis (Miroshnikova et al., 2018Miroshnikova Y.A. Le H.Q. Schneider D. Thalheim T. Rübsam M. Bremicker N. Polleux J. Kamprad N. Tarantola M. Wang I. et al.Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification.Nat. Cell Biol. 2018; 20: 69-80Crossref PubMed Scopus (135) Google Scholar), we show that, during homeostasis, differentiation of epithelial stem cells from the basal epidermal layer leads to neighboring cell size increase, cell cycle progression, and, ultimately, cell division. Finally, we show that experimentally induced exit from the stem cell compartment is sufficient to drive local stem cell self-renewal. Altogether, this study identifies differentiation as the homeostatic driver of stem cell self-renewal in the mammalian epidermis. To begin to interrogate homeostatic regulation of stem cell self-renewal, we examined whether this behavior was occurring randomly with relation to surrounding stem cell activity. To address this question, we needed the ability to track every cell fate decision and evaluate it in the context of all other stem cell behaviors taking place around it. We therefore developed a spatiotemporal map of all division and differentiation events occurring within a large region of tissue and over a long period of time. Building upon the live imaging approaches developed in our lab (Rompolas et al., 2012Rompolas P. Deschene E.R. Zito G. Gonzalez D.G. Saotome I. Haberman A.M. Greco V. Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration.Nature. 2012; 487: 496-499Crossref PubMed Scopus (256) Google Scholar, Pineda et al., 2015Pineda C.M. Park S. Mesa K.R. Wolfel M. Gonzalez D.G. Haberman A.M. Rompolas P. Greco V. Intravital imaging of hair follicle regeneration in the mouse.Nat. Protoc. 2015; 10: 1116-1130Crossref PubMed Scopus (43) Google Scholar), we devised a whole-tissue tracking approach based on serial revisits of the same epidermal tissue over time (Figure 1A). Using mice expressing epidermal cortical and nuclear fluorescent markers (K14-actinGFP [Vaezi et al., 2002Vaezi A. Bauer C. Vasioukhin V. Fuchs E. Actin cable dynamics and Rho/Rock orchestrate a polarized cytoskeletal architecture in the early steps of assembling a stratified epithelium.Dev. Cell. 2002; 3: 367-381Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar] and K14-H2BCerulean, respectively), we revisited the same epidermal regions every 12 hr for 7 days (Figures S1A and S1B). Unlike previous efforts that only followed selected cells (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar, Doupé et al., 2010Doupé D.P. Klein A.M. Simons B.D. Jones P.H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate.Dev. Cell. 2010; 18: 317-323Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Lim et al., 2013Lim X. Tan S.H. Koh W.L.C. Chau R.M.W. Yan K.S. Kuo C.J. van Amerongen R. Klein A.M. Nusse R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science. 2013; 342: 1226-1230Crossref PubMed Scopus (247) Google Scholar, Mascré et al., 2012Mascré G. Dekoninck S. Drogat B. Youssef K.K. Broheé S. Sotiropoulou P.A. Simons B.D. Blanpain C. Distinct contribution of stem and progenitor cells to epidermal maintenance.Nature. 2012; 489: 257-262Crossref PubMed Scopus (396) Google Scholar, Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar, Roy et al., 2016Roy E. Neufeld Z. Cerone L. Wong H.Y. Hodgson S. Livet J. Khosrotehrani K. Bimodal behaviour of interfollicular epidermal progenitors regulated by hair follicle position and cycling.EMBO J. 2016; 35: 2658-2670Crossref PubMed Scopus (31) Google Scholar, Sada et al., 2016Sada A. Jacob F. Leung E. Wang S. White B.S. Shalloway D. Tumbar T. Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin.Nat. Cell Biol. 2016; 18: 619-631Crossref PubMed Scopus (113) Google Scholar, Sánchez-Danés et al., 2016Sánchez-Danés A. Hannezo E. Larsimont J.C. Liagre M. Youssef K.K. Simons B.D. Blanpain C. Defining the clonal dynamics leading to mouse skin tumour initiation.Nature. 2016; 536: 298-303Crossref PubMed Scopus (70) Google Scholar), this approach, for the first time, accounts for the activity of every cell in a field of view and, thus, provides a complete record of activity in homeostasis. Combining this imaging with the development of a semi-automated tracking method, we recorded 1,527 divisions and 1,540 differentiation events, representing a comprehensive record of all epidermal cell fate decisions across six regions from five mice (Figure 1A; Video S1). https://www.cell.com/cms/asset/88f38a43-bb52-4276-8848-ea5488ee072b/mmc2.mp4Loading ... Download .mp4 (2.9 MB) Help with .mp4 files Video S1. Live Image Sequence of Nuclei in the Mouse Epidermis Basal Layer, Related to Figure 1Left: optical section of basal layer cells (K14-H2BCerulean) in a region of size 90 μm x 90 μm. Right: result of whole cell population tracking. Colors represent clones from the initial timepoint, and the regions of colors represent the voronoi diagram calculated from the position of the cells (local maxima in K14-H2BCerulean signal intensity). 1 frame = 12 hours. With these data, we were able to test whether stem cells might control their rates of self-renewal in response to differentiation of neighboring stem cells or vice versa. We reasoned that the record of division and differentiation events would show whether such control occurs rapidly, leading to instantaneous fate balance, or slowly, leading to a lag in fate balance. It would also reveal whether stem cells respond directly to the fate of neighboring cells or indirectly to the integrated activity of many stem cells (Yamaguchi et al., 2017Yamaguchi H. Kawaguchi K. Sagawa T. Dynamical crossover in a stochastic model of cell fate decision.Phys. Rev. E. 2017; 96: 012401Crossref PubMed Scopus (9) Google Scholar). Finally, such data could also reveal whether cell fate probabilities are “hard-wired” in epidermal tissue (e.g., as odds of a coin flip), as proposed previously (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar, Simons and Clevers, 2011Simons B.D. Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues.Cell. 2011; 145: 851-862Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). In such a case, each stem cell would commit to its fate in an autonomous manner, with division and differentiation remaining only balanced over large fields of cells by the law of large numbers. We first determined whether stem cells were compensating for the activity of their neighbors at all, and if so, how quickly they did this. For this, we focused on the extent to which division and differentiation behaviors were imbalanced over time. Although we observed both behaviors occurring in each imaged region and at each 12-hr time point, the number of cells dividing and differentiating over a given 12-hr period varied widely. Moreover, there was a significant discrepancy between the number of cells performing each activity between time points (Figures 1A and 1B), indicating the absence of any fast or instantaneous compensatory response of stem cells over this short interval. However, when we extended our analysis to a window of 7 days, we found that division and differentiation events occurred in nearly equal numbers, suggesting that stem cells might be responding to the activity of their neighbors over this longer period of time. Importantly, the imbalance between division and differentiation events in small regions of the tissue (22.5 μm × 22.5 μm) was significantly closer to zero than would be expected if each stem cell were autonomously deciding to divide or differentiate (SD about zero of 2.9 events versus 5.7 events, p < 0.0001; see STAR Methods for details). This ruled out the possibility that stem cell fates are autonomous in the epidermis, as proposed previously and modeled by us and others (Klein and Simons, 2011Klein A.M. Simons B.D. Universal patterns of stem cell fate in cycling adult tissues.Development. 2011; 138: 3103-3111Crossref PubMed Scopus (235) Google Scholar, Simons and Clevers, 2011Simons B.D. Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues.Cell. 2011; 145: 851-862Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar, Doupé et al., 2010Doupé D.P. Klein A.M. Simons B.D. Jones P.H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate.Dev. Cell. 2010; 18: 317-323Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Lim et al., 2013Lim X. Tan S.H. Koh W.L.C. Chau R.M.W. Yan K.S. Kuo C.J. van Amerongen R. Klein A.M. Nusse R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling.Science. 2013; 342: 1226-1230Crossref PubMed Scopus (247) Google Scholar, Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar). Instead, they appear to invoke mechanisms to actively balance their fates over time. We then asked whether stem cells were responding to their local neighbors or to a broad neighborhood by scoring how often a cell behavior (division or differentiation) is close to another behavior that is the same or the opposite. Interestingly, we found that, within a 2-day window, nearest neighbor pairs of fate decision points were more likely to be opposite fates than would be expected by random chance (Figures 1C and 1D) (p < 0.0001, permutation test). Correspondingly, direct neighbors that execute the same fates were found less frequently than expected. Such coordination became weaker when looking at next-nearest neighbors but was still significant. Consistent with our previous work (Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar), the fates of sibling pairs tended to be the same rather than the opposite. Together, these observations suggested that compensatory coordination between stem cell fates, which is key to balancing cell numbers over long periods of time, were occurring between neighboring pairs rather than between sibling pairs. To precisely quantify the timing and spatial extent over which stem cells sense and respond to activity in the tissue, we devised a quantitative test that reveals whether the imbalance between the number of division and differentiation events differs from a null “non-response” hypothesis over any given time interval and any area of tissue. The methodology of this test defines the imbalance between the number of division and differentiation events as a function of window size w and time t, ΔN(w,t) (Figure 2A). We quantified ΔN(w,t) at many different spatial positions and over time to calculate its fluctuation (or Var[ΔN(w,t)]) and then compared this fluctuation with a null hypothesis randomizing the location of all division and differentiation events (Figures S2A–S2C). Over a short time window (1 day) and after randomizing the location of all division and differentiation events, all cell fate choices appear to lack coordination, as expected (Figures 2B, 2C, S2D, and S2E). In contrast, at a 4-cell diameter (w = 4 cells, 27 μm), the variance of ΔN(w,t) departs clearly from random at later times (more than 2 days), indicating that stem cells are coordinating their behaviors within their local neighborhood (Figures 2B and 2C). Strikingly, even when considering smaller distances w and time periods of less than 3 days, the variance of ΔN(w,t) remains distinct from random (Figures 2B and 2C). Fitting Var[ΔN(w,t)] to a generalized stochastic model with a coordination length scale l and timescale τ, we found that the timescale of coordination was approximately 1 to 2 days, whereas its length scale corresponded to the size of a single cell (∼4 μm; Figures 2B, 2C, S2D, and S2E; see STAR Methods for detail of the analysis). Thus, homeostatic self-renewal and differentiation are balanced by stem cells counteracting the fate of their neighbors, with a lag time of 1–2 days. To test this local coordination of behaviors, we used a second method to mark and follow geometrically defined regions in the basal layer over time. We used a recently described photo-activatable fluorescent reporter (K14H2B-PAmCherry) (Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar) to label circular regions (50 μm in radius, 108 cells on average) designed to capture multiple local neighborhoods of stem cells and their first- and second-degree neighbors and followed them for 3 consecutive days (Figures 2D and S2G). By counting the cells in the basal and suprabasal layers at each time point, we obtained the rates of division and differentiation as 0.23 events per day per basal layer cell (Figure 2E), consistent with rates obtained from previous tracking methods (Rompolas et al., 2016Rompolas P. Mesa K.R. Kawaguchi K. Park S. Gonzalez D. Brown S. Boucher J. Klein A.M. Greco V. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis.Science. 2016; 352: 1471-1474Crossref PubMed Scopus (140) Google Scholar). As a quantitative measure of behavioral coordination, we calculated the variance in the number of labeled basal cells per patch. In the absence of any local fate coordination within labeled patches, each basal cell should undergo independent stochastic dynamics, as proposed previously (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (639) Google Scholar), leading to a linear increase in variance of approximately 80 cells2 after 3 days (Figure 2E). However, strikingly, we observed very little variation in the number of cells contained within each circle after 3 days (Figures 2F; variance of 22 cells2). This clear deviation from the behaviors predicted by independent stochastic dynamics confirms that stem cells are indeed responding by self-renewing and/or differentiating to counteract local changes in cell number (Figure 2G). So far, we have demonstrated that neighboring stem cells locally balance self-renewal and differentiation rates; however, it remained unclear whether this relationship was a result of divisions driving local differentiation, as observed in the developing epidermis (Miroshnikova et al., 2018Miroshnikova Y.A. Le H.Q. Schneider D. Thalheim T. Rübsam M. Bremicker N. Polleux J. Kamprad N. Tarantola M. Wang I. et al.Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification.Nat. Cell Biol. 2018; 20: 69-80Crossref PubMed Scopus (135) Google Scholar). To test for this scenario in the adult basal layer, we focused on individual cells that either divided or differentiated and followed the subsequent behaviors of the cells directly surrounding them (Figure 3A). To overcome the noise from simultaneous and highly frequent divisions and differentiations in the tissue (Figure 1A; Video S1), we needed to average over hundreds of fate choice events to determine the overall imbalance of fates taking place between neighbors. If cell division leads to the differentiation of a neighbor, then there should be a net imbalance of one extra differentiation event in the cells directly surrounding the original division, whereas the fates of neighbors surrounding a differentiating cell should, on average, be perfectly balanced (Figure 3B). These expectations reverse when differentiation leads to neighbor division, whereas a mixed scenario should lead to neighbor cell fate imbalances following both types of events (Figure 3B). Strikingly, the net imbalance across all dividing and differentiating cells showed a clear and unexpected unidirectional bias, with one excess stem cell division among cells directly neighboring a differentiation event but no reciprocal compensation around dividing cells (Figures 3C and S2F). Our results thus indicate that, in contrast to the embryonic scenario, homeostatic self-renewal in the adult epidermis is driven by neighboring stem cell differentiation events and not vice versa. To functionally test this ordering of events, we reasoned that, if differentiation is indeed a driver of self-renewal, then manipulations that cause ectopic differentiation events should lead to a later compensatory increase in division. To test this hypothesis, we employed epidermal tape stripping, a method known to promote epidermal differentiation events through removal of the outermost terminally differentiated layers of the skin (Potten et al., 2000Potten C.S. Barthel D. Li Y.Q. Ohlrich R. Matthé B. Loeffler M. Proliferation in murine epidermis after minor mechanical stimulation. Part 1. Sustained increase in keratinocyte production and migration.Cell Prolif. 2000; 33: 231-246Crossref PubMed Scopus (12) Google Scholar). Although this approach has long been known to also increase stem cell division (Pinkus, 1951Pinkus H. Examination of the epidermis by the strip method of removing horny layers. I. Observations on thickness of the horny layer, and on mitotic activity after stripping.J. Invest. Dermatol. 1951; 16: 383-386Abstract Full Text PDF PubMed Scopus (220) Google Scholar), whether this wave of proliferation occurs subsequent to altered differentiation rates is not known. Thus, we sought to test our model by using groups of K14H2B-PAmCherry-labeled cells to interrogate the sequence of events that occurs directly following tape stripping (Figure 4A). Tracking of labeled cells revealed a significant increase in differentiation rates within 12 hr of the procedure compared with unperturbed control cells (Figure 4B). Notably, although tape stripping also increased the abundance of mitotic figures in the tissue as expected, this effect occurred subsequent to the rise in differentiation (Figure 4C). We next predicted that, if differentiation is upstream and independent of s" @default.
• W2894486342 created "2018-10-05" @default.
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• W2894486342 date "2018-11-01" @default.
• W2894486342 modified "2023-10-17" @default.
• W2894486342 title "Homeostatic Epidermal Stem Cell Self-Renewal Is Driven by Local Differentiation" @default.
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