mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

doi:10.1016/j.stem.2017.11.008

. 2017 Dec 7;21(6):806-818.e5.

doi: 10.1016/j.stem.2017.11.008.

mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

Affiliations

¹ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
² Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
³ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Mount Holyoke College, South Hadley, MA 01075, USA.
⁴ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Medicine, Columbia University, New York, NY 10032, USA.
⁶ Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁷ Department of Anatomy, UCSF School of Medicine, San Francisco, CA 94117, USA.
⁸ Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC, Los Angeles, CA 90033, USA.
⁹ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Leibniz Institute on Aging, Fritz Lipmann Institute, Jena 07745, Germany. Electronic address: jasperh@gene.com.

PMID: 29220665
PMCID: PMC5823264
DOI: 10.1016/j.stem.2017.11.008

mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

Samantha Haller et al. Cell Stem Cell. 2017.

. 2017 Dec 7;21(6):806-818.e5.

doi: 10.1016/j.stem.2017.11.008.

Authors

Affiliations

¹ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
² Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
³ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Mount Holyoke College, South Hadley, MA 01075, USA.
⁴ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Medicine, Columbia University, New York, NY 10032, USA.
⁶ Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁷ Department of Anatomy, UCSF School of Medicine, San Francisco, CA 94117, USA.
⁸ Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC, Los Angeles, CA 90033, USA.
⁹ Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Leibniz Institute on Aging, Fritz Lipmann Institute, Jena 07745, Germany. Electronic address: jasperh@gene.com.

PMID: 29220665
PMCID: PMC5823264
DOI: 10.1016/j.stem.2017.11.008

Abstract

The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.

Keywords: Drosophila; aging; intestine; mTOR; metabolism; muscle; rapamycin; regeneration; somatic stem cell; trachea.

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Figures

Figure 1. Repeated regenerative events lead to Tor-dependent ISC loss in *Drosophila*
A. Schematic representation of TOR-mediated differentiation in the ISC lineage in *Drosophila*. Quiescent ISCs exhibit low TOR activity due to the expression of high levels of TSC2. In response to tissue damage, ISCs divide asymmetrically and induce differentiation in their EB daughters by triggering Notch signaling. The level of Notch signaling activity determined differentiation into either ECs (high Notch) or EEs (low Notch). Notch activation results in TOR activation through the transcriptional repression of TSC2 in EBs. This activation of TOR is sufficient and required for differentiation into ECs. B. Transient activation of ISC proliferation in response to *Erwinia Carotovora Carotovora* 15 (*Ecc15*) infection. Mitotic figures in whole intestines of wild type flies and flies expressing double-stranded RNA against dRaptor (dRaptor^RNAi), exposed to *Ecc15* for the indicated time-points are quantified using phosphorylated Histone H3 (pH3) as a marker. For each time-point, data points represent the average +/− SEM (n≥9) in a representative experiment. ANOVA U-test. Only female flies between 4 and 8 days of age were used for these experiments. C, C′. Quantification of phospho-4EBP in ISCs (C) and confocal images of the middle posterior midgut (C′, region R4 is depicted) of flies expressing EYFP (green) in ISCs specifically (esg::Gal4, UAS::EYFP, Su(H)::Gal80) at indicated time-points after *Ecc15* infection. TOR activity is detected by immunohistochemistry against phospho-4EBP (p4EBP, red in upper panels, white in lower panels). Panels on the right show equivalent stainings at 17 hours after infection in flies over-expressing TSC1 and TSC2 (esg::Gal4, UAS::EYFP, Su(H)::Gal80/UAS::TSC1, UAS::TSC2) or a double-stranded RNA against TSC1 (TSC1^RNAi). Wild-type (WT) represents F1 of cross into the VDRC ID# 60000 control background. For each time-point and genotype n≥8 flies; representative images of one of at least three independent experiments are shown. Quantification of p-4EBP levels are mean fluorescence intensity in ISCs normalized to background. Bars represent the mean +/− SEM (n>10). One-way ANOVA. Only female flies between 4 and 8 days of age were used for these experiments. D. Analysis of ISC cell size in flies of the indicated genotypes exposed to *Ecc15* for the indicated timepoints (left panel). For each time-point and genotype, data points represent the mean +/− SEM (n≥8). On the right, analysis of the ISC cell size at 17h post Ecc15 infection, in wild type flies or in flies over-expressing TSC1 and 2 or double-stranded RNA against TSC1 in ISCs. Bars represent the mean +/− SEM (n>10). One-way ANOVA. E. Protocol for repeated *Ecc15* infections. Flies were transferred to 29°C prior to the first *Ecc15* infection in order to induce the expression of transgenes, and then kept subsequently at 29°C. F. Quantification of ISC numbers after repeated regenerative episodes. For each time-point and genotype, data points represent the number of ISCs per square (of 100×100μm) in separate guts. Red lines represent the median. ANOVA U-test. G. Quantification of ISC numbers after three regenerative episodes in wild type flies or in flies over-expressing TSC1 and 2 or double-stranded RNA against TSC1 in ISCs. Data points represent the mean per animal, the red line indicate the median. ANOVA U-test. H. Quantification of ISC numbers after three pulses of 29°C (24h per pulse, spaced by 5 days of 18°C) in wild type flies or flies over-expressing a double-stranded RNA against TSC1 in a temperature-inducible manner (tub::Gal80^ts). Data points represent the mean per animal, the red line indicates the median. ANOVA U-test. I. Quantification of ISCs (YFP expression), EEs (prospero) and ECs (pdm1) present per square of 100 X 100μm in the middle posterior midgut of wild type flies, or flies over-expressing TSC1 and 2 or double-stranded RNA against TSC1 in ISCs after three regenerative episodes induced by *Ecc15* infection. Results are expressed as a percentage of total cells. Data represent the means +/− SEM (n>8). ANOVA U-test. See also Figure S1.

**Figure 2. Tor signaling is induced in BCs upon regeneration and promotes differentiation**
A. Schematic representation of the basal cell (BC) lineage in the tracheal epithelium. BCs (characterized by Krt5 and Trp63 expression) are mostly quiescent, but are activated upon epithelial damage, expressing either N2ICD (committed to the secretory cell lineage) or c-myb (ciliated cell lineage). These cells transition to basal luminal progenitors (BLPs), which express both Keratin5 (Krt5) and Keratin 8 (Krt8). Similar to *Drosophila* ISCs, BCs and BLPs express Notch ligands (Jag2 and Dll1) to activate Notch in early precursors (EPs) and induce their differentiation into Secretory Cells (CCSP expressing). Secretory Cells have the ability to divide and terminally differentiate into Ciliated Cells (acetylated Tubulin, AcTub). B. Confocal images of the proximal tracheal epithelium after SO₂ treatment. Mice were exposed to SO₂ for 3 hours to ablate differentiated cells of the epithelium. Trachea were collected at 1, 3 and 8 days after SO₂ exposure. BC markers Trp63 and Krt5, the differentiated cell marker Krt8, and markers of stem cell activity (Ki67) and of Tor signaling activity (pS6) were detected by immunohistochemistry (IHC). For each time-point, panels show one representative epithelial section (SO₂ treated n=5 mice; n=3 controls). Arrowheads highlight Trp63+ BCs. C. Quantification of the number of cells expressing both Krt5 and Krt8. For each time-point, each data point represents the fraction of Krt8+ cells among all Krt5+ cells for one trachea. Red lines represent the median. One-way ANOVA. D. Quantification of the levels of pS6 in BCs during epithelial regeneration either by quantifying the IHC signal intensities or by western blot (WB on the whole trachea). Through IHC quantification pS6 intensity has been measured in BCs and normalized to the background. Through WB, pS6 levels have been normalized to the levels of total S6. For both graphs, data is represented as mean +/− SEM (n≥3). One-way ANOVA. E. Analysis of BC size in the airway epithelium after SO₂ exposure. For each time-point data is represented as mean +/− SEM (SO₂ treated n=5; Controls n=3). One-way ANOVA. F. Confocal images of a representative tracheosphere grown for 10 days. Spheres were stained for a BC marker (Trp63, green) and a marker of Tor activity (p4EBP, red). DAPI is shown in blue. Note high levels of p4EBP in cells emerging from the basal layer. G. Confocal images of tracheospheres treated with Rapamycin (200nM) for 6 days. Spheres were stained for a BC marker (Trp63, green) and a differentiated cell marker (Krt8, red). DAPI is shown in blue. Panels show one representative out of n≥50 spheres. Note the loss of pseudostratification in the sphere epithelium after Rapamycin treatment. H. Analysis of sphere size with or without Rapamycin treatment. Each data point represents the mean of sphere sizes from one trachea. Red lines represent the median of independent wells. ANOVA U-test. I. Quantification of BC numbers (% Trp63+ cells of all cells) in spheres with or without Rapamycin treatment. Each bar represents the mean +/− SEM (n=6). ANOVA U-test. See also Figure S2.

**Figure 3. Loss of tracheal BCs after repeated regenerative episodes and after chronic activation of Tor signaling**
A. Confocal images of an area of the tracheal epithelium after one SO2 (1× SO2) exposure or three SO₂ exposures (3× SO2, exposure performed every other week) in controls and Rapamycin treated mice, and corresponding quantification. Trp63 shown in green and grayscale, DAPI in blue. Each data point represents the mean for one trachea. Red lines represent the median. ANOVA U-test. B. TSC1 deletor mice (Krt5::Cre^ERT2, Rosa26::lacZ/TSC1^fl/fl) or controls (Krt5::Cre^ERT2, Rosa26::lacZ/+) were injected 3 or 4 times intra-peritoneally (IP) with Tamoxifen (one injection every other day) to induce TSC1 deletion specifically in BCs. Animals were euthanized and trachea collected at 10 days, 28 days (4 injections of Tamoxifen) and 40 days (3 injections of Tamoxifen) post Tamoxifen injection, respectively. Confocal images of the central region of the airway epithelium. IHC was performed to detect Trp63 (green), Krt8 (white in left panels), p-S6 (red in left, white in right panels), as well as phospho-Histone H3 to detect mitotic cells (not shown). Images show a representative epithelium of n≥4 samples analyzed. C. The percent of Trp63+ cells expressing high levels of pS6, the size of Trp63+ cells (in pixels), the number of pH3+ cells in the whole trachea and the proportion of secretory (CCSP+) and ciliated (AcTub) cells are represented. Each data point represents the mean for one trachea. Red lines represent the median. ANOVA U-test. D. Confocal images of an area of the tracheal epithelium and quantifications of Krt5+/Krt8+ double-positive BLPs at the indicated timepoints after SO₂ exposure in controls (Krt5::Cre^ERT2, Rosa26::lacZ/+) or TSC1 deletor mice (Krt5::Cre^ERT2, Rosa26::lacZ/TSC1^fl/fl). IHC detecting Krt5 (green) and Krt8 (red and white). One representative epithelium (n≥5 for 8 day sample is shown). Yellow arrows indicate Krt5 only, while red arrows indicate Krt5/Krt8 double positive cells. D′. Corresponding quantifications. Each data point represents the mean for one trachea. Red lines represent the median. One-way ANOVA. E. Brightfield images of X-Gal and Hematoxylin/Eosin stained tracheal epithelia of control (Krt5::Cre^ERT2, Rosa26::lacZ/+) or TSC1 deletor mice (Krt5::Cre^ERT2, Rosa26::lacZ/TSC1^fl/fl) at indicated timepoints after Tamoxifen injection. X-Gal and IHC against Krt5 (in black) shown in lower panels. Pictures show one representative stained epithelium (n≥4). F. Quantification of BC numbers in confocal sections at indicated times after the last Tamoxifen injection. Each data point represents the mean per trachea +/− SEM (n≥4). One-way ANOVA. G. Confocal images of an area of the tracheal epithelium at 40 days after Tamoxifen treatment of controls (Krt5::Cre^ERT2, Rosa26::eYFP/+) or TSC1 deletor mice (Krt5::Cre^ERT2, Rosa26::eYFP/TSC1^fl/fl), and the corresponding quantifications (%) of eYFP clones containing BCs (Krt5+) and the different cell types present in the eYFP clones (BCs, Secretory and Ciliated cells). Each data point (quantification of clones containing BCs) represents the mean for one trachea. Red lines represent the median (n≥5). Bars (cell type analysis) represent the mean +/− SEM (n>4). ANOVA U-test. H. Quantification of Trp63+ cells (BCs) in tracheospheres derived from control (Krt5::Cre^ERT2, Rosa26::lacZ/+) or TSC1 deletor mice (Krt5::Cre^ERT2, Rosa26::lacZ/TSC1^fl/fl). Spheres were grown for 9 days, then exposed to Tamoxifen for 2 days. Each data point represents the mean for one sphere. Red lines represent the median. One-way ANOVA. See also Figure S3.

**Figure 4. Accumulation of BLPs in the regenerating old tracheal epithelium**
A. Quantifications of Krt5+/Krt8+ cells in young (4 months old), old (20 months old) and old Rapamycin treated (3 month of Rapamycin, 42ppm) epithelia after SO₂ exposure. Each data point represents the mean for one trachea. Red lines represent the median. One-way ANOVA. B. Quantifications of Ki67+ cells in young (4 months old), old (20 months old) and old Rapamycin treated (3 month of Rapamycin 42ppm) epithelia after SO₂ exposure. Each data point represents the mean for one trachea. Red lines represent the median. One-way ANOVA. See also Figure S4.

**Figure 5. Chronic repression of Tor signaling rescues the loss of BCs observed in old mice**
A. Schematic of Rapamycin exposure for chronic repression of Tor. Mice were fed Rapamycin for 3 months starting either at 9 or 15 month of age, or for 12 months starting at 12 month of age. B. Bright field images of H&E stained airway epithelium of young (3 months old), old (24 months old) and old Rapamycin-treated (24 months old exposed to Rapamycin food for 12 months) mice. C. Confocal images of an area of the airway epithelium of young (3 months old), old (24 months old) and old Rapamycin-treated (24 months old exposed to Rapamycin food for 12 months) mice. IHC against Trp63 (white and green) and Krt8 (red). Upper panels are low magnification (5×) showing most of the trachea, lower panels are high magnification (40×) showing a section of the tracheal epithelium. D. Quantification of BCs (Trp63+) in the airway epithelium of either young or old mice with or without Rapamycin treatment. Genotypes of all mice were C57BL/6J with the exception of the mice analyzed at 9+3 months, which were FVB/N. Averages and SEM are shown, Student’s Ttest (1 month old: n=4; 9+3 months: n=4 Control and n=3 Rapamycin; 12+12 months: n=2 Control and n=6 Rapamycin). E. Quantification of Krt8+/Trp63+ double-positive cells in tracheospheres derived from 1 month or 18 month old mice that were fed Rapamycin containing or control food for 3 months (15+3). Averages and SEM are shown, Student’s Ttest. n=5 mice at 1 month old, N= 10 mice for 18 months old samples. 6–10 Spheres per mouse were quantified. F. Schematic outline of the timecourse of Tmx treatment and euthanizing of mice at young, adult, and aged timepoints in Control mice (Pax7^CreER/+; Rosa26^EYFP/+), MuSCs TSC1 cKO mice (TSC1^flox/flox;Pax7^CreER/+;Rosa26^EYFP/+) and MuSC Rptr cKO mice (Rptr1^flox/flox;Pax7^CreER/+;Rosa26^EYFP/+). YFP⁺-Pax7⁺ MuSC were quantified by IHC staining of tibial anterior (TA) muscle cross-sections and normalized to the number of muscle fibers in a field. Each data point represents the mean for one animal (n≥4). See also Figure S5.

**Figure 6. Model for the role of repeated transient mTORC1 activation events resulting in progressive BC loss in aging epithelia**
Upon regeneration, stem cells transiently activate mTORC1 signaling in order to rapidly repair the tissue. Stochastically, some stem cells fail to down regulate mTORC1 activity after regeneration and are driven to differentiation, resulting in loss of stem cells. Repeated regenerative episodes during the life-time of an animal thus results in a loss of BCs that can be reversed by chronic supplementation with Rapamycin.

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Comment in

Regeneration of injured tissue: stem cell dynamics at interplay with mTORC1.
Mikula M. Mikula M. Stem Cell Investig. 2018 Aug 30;5:27. doi: 10.21037/sci.2018.08.01. eCollection 2018. Stem Cell Investig. 2018. PMID: 30221172 Free PMC article. No abstract available.

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References

1. Amcheslavsky A, Ito N, Jiang J, Ip YT. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol. 2011;193:695–710. - PMC - PubMed
1. Ayyaz A, Jasper H. Intestinal inflammation and stem cell homeostasis in aging. Frontiers in cellular and infection microbiology. 2013;3:98. - PMC - PubMed
1. Ayyaz A, Li H, Jasper H. Haemocytes control stem cell activity in the Drosophila intestine. Nat Cell Biol. 2015;17:736–748. - PMC - PubMed
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1. Biteau B, Hochmuth CE, Jasper H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell. 2011;9:402–411. - PMC - PubMed

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[1] Amcheslavsky A, Ito N, Jiang J, Ip YT. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol. 2011;193:695–710. - PMC - PubMed

[2] Amcheslavsky A, Ito N, Jiang J, Ip YT. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol. 2011;193:695–710. - PMC - PubMed

[3] Ayyaz A, Jasper H. Intestinal inflammation and stem cell homeostasis in aging. Frontiers in cellular and infection microbiology. 2013;3:98. - PMC - PubMed

[4] Ayyaz A, Jasper H. Intestinal inflammation and stem cell homeostasis in aging. Frontiers in cellular and infection microbiology. 2013;3:98. - PMC - PubMed

[5] Ayyaz A, Li H, Jasper H. Haemocytes control stem cell activity in the Drosophila intestine. Nat Cell Biol. 2015;17:736–748. - PMC - PubMed

[6] Ayyaz A, Li H, Jasper H. Haemocytes control stem cell activity in the Drosophila intestine. Nat Cell Biol. 2015;17:736–748. - PMC - PubMed

[7] Biteau B, Hochmuth CE, Jasper H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell. 2008;3:442–455. - PMC - PubMed

[8] Biteau B, Hochmuth CE, Jasper H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell. 2008;3:442–455. - PMC - PubMed

[9] Biteau B, Hochmuth CE, Jasper H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell. 2011;9:402–411. - PMC - PubMed

[10] Biteau B, Hochmuth CE, Jasper H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell. 2011;9:402–411. - PMC - PubMed

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mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

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mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

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