Year: 2020
Type: editorial
Abstract: In this issue of Cellular and Molecular Gastroenterology and Hepatology, Bohin et al1Bohin N. McGowan K.P. Keeley T.M. Carlson E.A. Yan K.S. Samuelson L.C. Insulin-like growth factor-1 and mTORC1 signaling promote the intestinal regenerative response after irradiation injury.Cell Mol Gastroenterol Hepatol. 2020; 10: 797-810Abstract Full Text Full Text PDF Scopus (2) Google Scholar identify insulin-like growth factor-1 (Igf1) as regulator of mTorc1-dependent facultative intestinal stem cell (FSC) activation and epithelial barrier regeneration in response to DNA damaging injury. The columnar epithelium of the intestinal tract is not only the body’s highest turnover tissue; it is also remarkably capable of regeneration in response to high doses of DNA damaging injury. Over the past 15 years, mouse studies using an array of lineage tracing strategies have led to a model of the intestinal stem cell compartment in which active crypt base columnar (CBC) stem cells driven by canonical Wnt-β-catenin signaling maintain homeostatic turnover, yet they are readily ablated by DNA damaging injury.2Tao S. Tang D. Morita Y. Sperka T. Omrani O. Lechel A. Sakk V. Kraus J. Kestler H.A. Kühl M. Rudolph K.L. Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage.EMBO J. 2017; 36: 2920-2921Crossref PubMed Scopus (5) Google Scholar In the face of such injury, an extremely rare and poorly defined pool of FSCs, likely within the secretory lineage, can reenter the CBC state to drive rapid epithelial regeneration and barrier restoration.3Bankaitis E.D. Ha A. Kuo C.J. Magness S.T. Reserve stem cells in intestinal homeostasis and injury.Gastroenterology. 2018; 155: 1348-1361Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 4Li L. Clevers H. Coexistence of quiescent and active adult stem cells in mammals.Science. 2010; 327: 542-545Crossref PubMed Scopus (841) Google Scholar, 5Yousefi M. Li L. Lengner C.J. Hierarchy and plasticity in the intestinal stem cell compartment.Trends Cell Biol. 2017; 27: 753-764Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The molecular mechanisms governing the resistance of FSCs to DNA damage-induced death and their subsequent reacquisition of CBC identity remain poorly understood. Here, Bohin et al1Bohin N. McGowan K.P. Keeley T.M. Carlson E.A. Yan K.S. Samuelson L.C. Insulin-like growth factor-1 and mTORC1 signaling promote the intestinal regenerative response after irradiation injury.Cell Mol Gastroenterol Hepatol. 2020; 10: 797-810Abstract Full Text Full Text PDF Scopus (2) Google Scholar identify dramatic increases in Igf1 levels in the subepithelial mesenchyme in response to DNA damaging injury (using a standard experimental paradigm of 12 Gy ionizing radiation). The peak of Igf1 expression is coincident with the earliest FSC divisions, about 48 hours after injury, and treatment with small molecule inhibitors of the Igf1 receptor (Igfr) abrogates the epithelial regenerative response. Interestingly, the subepithelial source of Igf acting on Igf1r-expressing epithelial cells may be the recently described Foxl1+ telocytes,6Aoki R. Shoshkes-Carmel M. Gao N. Shin S. May C.L. Golson M.L. Zahm A.M. Ray M. Wiser C.L. Wright C.V.E. Kaestner K.H. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche.Cell Mol Gastroenterol Hepatol. 2016; 2: 175-188Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar,7Kaestner K.H. The intestinal stem cell niche: a central role for foxl1-expressing subepithelial telocytes.Cell Mol Gastroenterol Hepatol. 2019; 8: 111-117Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar which are responsible for generating the WntHigh niche for CBCs during normal homeostasis. Indeed, telocytes appear unique in their expression of Igf1 among cells of the mucosa,8Shoshkes-Carmel M. Wang Y.J. Wangensteen K.J. Tóth B. Kondo A. Massasa E.E. Itzkovitz S. Kaestner K.H. Subepithelial telocytes are an important source of Wnts that supports intestinal crypts.Nature. 2018; 557: 242-246Crossref PubMed Scopus (164) Google Scholar yet how telocytes respond to insults and how their response shapes epithelial function remain unknown. Igf/Igfr signaling acts upstream of both the Ras/ERK pathway and the PI3K/AKT/mTorc1 pathway. Using a combination of genetic and pharmacologic approaches, Bohin et al1Bohin N. McGowan K.P. Keeley T.M. Carlson E.A. Yan K.S. Samuelson L.C. Insulin-like growth factor-1 and mTORC1 signaling promote the intestinal regenerative response after irradiation injury.Cell Mol Gastroenterol Hepatol. 2020; 10: 797-810Abstract Full Text Full Text PDF Scopus (2) Google Scholar go on to dissect the requirement for mTorc1 activity for FSC activation. They find that mTorc1 inhibition with rapamycin before, but not after, initial FSC activation abrogates regeneration and lineage tracing from Bmi1CreER-marked FSCs. These data add to a growing body of literature describing a requirement for mTorc1 during FSC activation and regeneration in response to DNA damaging injury. Recently, a related study9Yousefi M. Nakauka-Ddamba A. Berry C.T. Li N. Schoenberger J. Simeonov K.P. Cedeno R.J. Yu Z. Lengner C.J. Calorie restriction governs intestinal epithelial regeneration through cell-autonomous regulation of mTORC1 in reserve stem cells.Stem Cell Rep. 2018; 10: 703-711Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar observed that mTorc1 activity in FSCs could be potently stimulated through dietary leucine; if leucine is given before DNA damaging injury, FSCs become prematurely activated, enter the cell cycle, and undergo DNA damage-induced apoptosis, resulting in compromised regeneration. Conversely, if mTorc1 is inhibited via caloric restriction before DNA damage, a larger pool of FSCs is available to enhance the regenerative response. In contrast, and consistent with the current study, inhibition of mTorc1 with rapamycin immediately before or after injury abrogates regeneration, despite protecting FSCs against apoptosis. We may interpret these findings as mTorc1 inhibition via caloric restriction being readily reversible in response to injury, in contrast to the effects of rapamycin. In another related and consistent study, Richmond et al10Richmond C.A. Shah M.S. Deary L.T. Trotier D.C. Thomas H. Ambruzs D.M. Jiang L. Whiles B.B. Rickner H.D. Montgomery R.K. Tovaglieri A. Carlone D.L. Breault D.T. Dormant intestinal stem cells are regulated by PTEN and nutritional status.Cell Rep. 2015; 13: 2403-2411Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar observe that acute fasting increases the pool of FSCs (in this instance marked by mTert-CreER or -GFP reporters), that this pool of cells has increased Pten phosphatase protein activity (an upstream inhibitor of mTorc1), and that refeeding after fasting results in mTorc1 activation in FSCs. Furthermore, Pten phosphatase protein–deficient intestines have a compromised regenerative response to DNA damage, illustrating how the timing and balance of mTorc1 activity dictate the response to injury. In aggregate, these studies support a model where a pool of FSCs is maintained in a highly DNA damage-resistant state with low mTorc1 activity. These FSCs must activate mTorc1 to enter the cell cycle and regenerate the epithelium in response to DNA damage that ablates cycling CBCs and progenitors. Importantly, the cues acutely inducing mTorc1 at the correct time after DNA damage are likely acting via signal transduction pathways (eg, the Igf/Igfr axis proposed by Bohin et al1Bohin N. McGowan K.P. Keeley T.M. Carlson E.A. Yan K.S. Samuelson L.C. Insulin-like growth factor-1 and mTORC1 signaling promote the intestinal regenerative response after irradiation injury.Cell Mol Gastroenterol Hepatol. 2020; 10: 797-810Abstract Full Text Full Text PDF Scopus (2) Google Scholar). However nutrient-sensing inputs into mTorc1 are similarly able to control FSC activation and modulate the regenerative response to DNA damaging injury. Thus, although caloric restriction or fasting might better poise the epithelium to respond to a future injury, acute growth factor stimulation might enhance the regenerative process after injury. Although these studies are beginning to provide insight into the molecular control of FSC activity, this remains a challenging area of research. FSCs are exceedingly rare on the basis of their functional definition: the ability to form a clonal regenerative crypt after injury, which ablates the cycling stem/progenitor compartment. They also remain poorly defined molecularly because they are present at greater or lesser frequency in populations marked by Bmi1-CreER, mTert-CreER, Hopx-CreER, and numerous other, more widely active CreER drivers. To date, no single CreER allele has been identified that marks a homogenous population of functional FSCs required for epithelial regeneration, making the prospective identification and study of these powerful cells an ongoing challenge. Insulin-like Growth Factor-1 and mTORC1 Signaling Promote the Intestinal Regenerative Response After Irradiation InjuryCellular and Molecular Gastroenterology and HepatologyVol. 10Issue 4PreviewIntestinal crypts have a remarkable capacity to regenerate after injury from loss of crypt base columnar (CBC) stem cells. After injury, facultative stem cells (FSCs) are activated to replenish the epithelium and replace lost CBCs. Our aim was to assess the role of insulin-like growth factor-1 (IGF-1) to activate FSCs for crypt repair. Full-Text PDF Open Access
Author: Christopher J. Lengner
Institution: University of Pennsylvania
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W3048673789