2021 review
Secretory Sorcery: Paneth Cell Control of Intestinal Repair and Homeostasis
[Review of ]. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 12(4), 1239–1250.
Paneth cells are professional secretory cells that classically play a role in the innate immune system by secreting antimicrobial factors into the lumen to control enteric bacteria. In this role, Paneth cells are able to sense cues from luminal bacteria and respond by changing production of these factors to protect the epithelial barrier. Paneth cells rely on autophagy to regulate their secretory capability and capacity. Disruption of this pathway through mutation of genes, such as Atg16L1, results in decreased Paneth cell function, dysregulated enteric microbiota, decreased barrier integrity, and increased risk of diseases such as Crohn's disease in humans. Upon differentiation Paneth cells migrate downward and intercalate among active intestinal stem cells at the base of small intestinal crypts. This localization puts them in a unique position to interact with active intestinal stem cells, and recent work shows that Paneth cells play a critical role in influencing the intestinal stem cell niche. This review discusses the numerous ways Paneth cells can influence intestinal stem cells and their niche. We also highlight the ways in which Paneth cells can alter cells and other organ systems. Paneth cells are professional secretory cells that classically play a role in the innate immune system by secreting antimicrobial factors into the lumen to control enteric bacteria. In this role, Paneth cells are able to sense cues from luminal bacteria and respond by changing production of these factors to protect the epithelial barrier. Paneth cells rely on autophagy to regulate their secretory capability and capacity. Disruption of this pathway through mutation of genes, such as Atg16L1, results in decreased Paneth cell function, dysregulated enteric microbiota, decreased barrier integrity, and increased risk of diseases such as Crohn's disease in humans. Upon differentiation Paneth cells migrate downward and intercalate among active intestinal stem cells at the base of small intestinal crypts. This localization puts them in a unique position to interact with active intestinal stem cells, and recent work shows that Paneth cells play a critical role in influencing the intestinal stem cell niche. This review discusses the numerous ways Paneth cells can influence intestinal stem cells and their niche. We also highlight the ways in which Paneth cells can alter cells and other organ systems. SummaryTheir position at the crypt base puts Paneth cells in a unique position to interact with active intestinal stem cells and influence the intestinal stem cell niche. However, they also interact with other cells and organ systems and possess the ability to take on stem cell-like characteristics under certain circumstances. Their position at the crypt base puts Paneth cells in a unique position to interact with active intestinal stem cells and influence the intestinal stem cell niche. However, they also interact with other cells and organ systems and possess the ability to take on stem cell-like characteristics under certain circumstances. Paneth cells (PCs) are professional secretory cells that are named after Josef Paneth, who was among the first to describe these cells.1Trier J.S. The paneth cells: an enigma.Gastroenterology. 1966; 51: 560-562Abstract Full Text PDF PubMed Google Scholar PCs are intercalated between active intestinal stem cells (aISCs) in the small intestine (SI) of those species that have PCs, including mice and humans.2Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration.Nat Rev Mol Cell Biol. 2014; 15: 19-33Crossref PubMed Scopus (627) Google Scholar Some species (such as dogs) do not have PCs, whereas other species (such as horses and anteaters) have large numbers of PCs per crypt.3Bruhn O. Grötzinger J. Cascorbi I. Jung S. Antimicrobial peptides and proteins of the horse: insights into a well-armed organism.Vet Res. 2011; 42: 98Crossref PubMed Scopus (39) Google Scholar PCs are long-lived differentiated secretory cells that do not migrate up the crypt-villus axis, unlike other differentiated cell types.4Ireland H. Houghton C. Howard L. Winton D.J. Cellular inheritance of a Cre-activated reporter gene to determine paneth cell longevity in the murine small intestine.Dev Dyn. 2005; 233: 1332-1336Crossref PubMed Scopus (86) Google Scholar It has been shown that PCs provide a support system for the aISCs by expressing Notch ligands5Pellegrinet L. Rodilla V. Liu Z. Chen S. Koch U. Espinosa L. Kaestner K.H. Kopan R. Lewis J. Radtke F. Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells.Gastroenterology. 2011; 140: 1230-1240.e7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and secreting molecules such as Wnt3a, epidermal growth factor (EGF),6Poulsen S.S. Nexø E. Skov Olsen P. Hess J. Kirkegaard P. Immunohistochemical localization of epidermal growth factor in rat and man.Histochemistry. 1986; 85: 389-394Crossref PubMed Scopus (189) Google Scholar,7Sato T. van Es J.H. Snippert H.J. Stange D.E. Vries R.G. van den Born M. Barker N. Shroyer N.F. van de Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1507) Google Scholar and lactate.8Rodríguez-Colman M.J. Schewe M. Meerlo M. Stigter E. Gerrits J. Pras-Raves M. Sacchetti A. Hornsveld M. Oost K.C. Snippert H.J. Verhoeven-Duif N. Fodde R. Burgering B.M.T. Interplay between metabolic identities in the intestinal crypt supports stem cell function.Nature. 2017; 543: 424-427Crossref PubMed Scopus (203) Google Scholar Thus, these cells remain at the crypt base. PCs can sense calorie restriction, which drives stem cell proliferation via mammalian target of rapamycin (mTOR) inhibition.9Yilmaz Ö.H. Katajisto P. Lamming D.W. Gültekin Y. Bauer-Rowe K.E. Sengupta S. Birsoy K. Dursun A. Yilmaz V.O. Selig M. Nielsen G.P. Mino-Kenudson M. Zukerberg L.R. Bhan A.K. Deshpande V. Sabatini D.M. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.Nature. 2012; 486: 490-495Crossref PubMed Scopus (431) Google Scholar PCs also control the site of crypt fission, pushing the more malleable aISCs out of the crypt base to form new crypt invaginations.10Langlands A.J. Almet A.A. Appleton P.L. Newton I.P. Osborne J.M. Näthke I.S. Paneth cell-rich regions separated by a cluster of Lgr5+ cells initiate crypt fission in the intestinal stem cell niche.PLOS Biol. 2016; 14e1002491Crossref PubMed Scopus (39) Google Scholar PCs perform numerous functions in homeostasis, including antimicrobial protein secretion,11Erlandsen S.L. Parsons J.A. Taylor T.D. Ultrastructural immunocytochemical localization of lysozyme in the Paneth cells of man.J Histochem Cytochem. 1974; 22: 401-413Crossref PubMed Google Scholar, 12Nevalainen T.J. Grönroos J.M. Kallajoki M. Expression of group II phospholipase A2 in the human gastrointestinal tract.Lab Investig J Tech Methods Pathol. 1995; 72: 201-208PubMed Google Scholar, 13Porter E.M. Liu L. Oren A. Anton P.A. Ganz T. Localization of human intestinal defensin 5 in Paneth cell granules.Infect Immun. 1997; 65: 2389-2395Crossref PubMed Google Scholar modulation of the small intestinal microbiota,14Burger E. Araujo A. López-Yglesias A. Rajala M.W. Geng L. Levine B. Hooper L.V. Burstein E. Yarovinsky F. Loss of Paneth cell autophagy causes acute susceptibility to Toxoplasma gondii-mediated inflammation.Cell Host Microbe. 2018; 23: 177-190.e4Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,15Gulati A.S. Shanahan M.T. Arthur J.C. Grossniklaus E. Furstenberg RJ von Kreuk L. Henning S.J. Jobin C. Sartor R.B. Mouse background strain profoundly influences Paneth cell function and intestinal microbial composition.PLOS One. 2012; 7e32403Crossref PubMed Scopus (59) Google Scholar and immune surveillance.16Vaishnava S. Behrendt C.L. Ismail A.S. Eckmann L. Hooper L.V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.Proc Natl Acad Sci. 2008; 105: 20858-20863Crossref PubMed Scopus (0) Google Scholar To manage this secretory capacity, PCs have an expanded endoplasmic reticulum (ER) network and rely heavily on autophagy and the unfolded protein response (UPR).17Cadwell K. Liu J.Y. Brown S.L. Miyoshi H. Loh J. Lennerz J.K. Kishi C. Kc W. Carrero J.A. Hunt S. Stone C.D. Brunt E.M. Xavier R.J. Sleckman B.P. Li E. Mizushima N. Stappenbeck T.S. Virgin H.W. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1076) Google Scholar,18Jones E.J. Matthews Z.J. Gul L. Sudhakar P. Treveil A. Divekar D. Buck J. Wrzesinski T. Jefferson M. Armstrong S.D. Hall L.J. Watson A.J.M. Carding S.R. Haerty W. Palma F.D. Mayer U. Powell P.P. Hautefort I. Wileman T. Korcsmaros T. Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy.Dis Model Mech. 2019; 12Google Scholar This puts PCs at risk for ER stress, and PC-specific genetic defects in autophagy are related to inflammatory bowel diseases.17Cadwell K. Liu J.Y. Brown S.L. Miyoshi H. Loh J. Lennerz J.K. Kishi C. Kc W. Carrero J.A. Hunt S. Stone C.D. Brunt E.M. Xavier R.J. Sleckman B.P. Li E. Mizushima N. Stappenbeck T.S. Virgin H.W. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.Nature. 2008; 456: 259-263Crossref PubMed Scopus (1076) Google Scholar,19Liu B. Gulati A.S. Cantillana V. Henry S.C. Schmidt E.A. Daniell X. Grossniklaus E. Schoenborn A.A. Sartor R.B. Taylor G.A. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2013; 305: G573-G584Crossref PubMed Scopus (28) Google Scholar Metaplastic PCs in regions other than the SI (colon, stomach) are related to chronic inflammatory states.20Cunliffe R.N. Rose F.R. Keyte J. Abberley L. Chan W.C. Mahida Y.R. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease.Gut. 2001; 48: 176-185Crossref PubMed Scopus (176) Google Scholar PCs can also dedifferentiate after intestinal damage induced by doxorubicin (DXR) or irradiation (IR).21Hayakawa Y. Tsuboi M. Asfaha S. Kinoshita H. Niikura R. Konishi M. Hata M. Oya Y. Kim W. Middelhoff M. Hikiba Y. Higashijima N. Ihara S. Ushiku T. Fukayama M. Tailor Y. Hirata Y. Guha C. Yan K.S. Koike K. Wang T.C. BHLHA15-positive secretory precursor cells can give rise to tumors in intestine and colon in mice.Gastroenterology. 2019; 156: 1066-1081.e16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 22Jones J.C. Brindley C.D. Elder N.H. Myers M.G. Rajala M.W. Dekaney C.M. McNamee E.N. Frey M.R. Shroyer N.F. Dempsey P.J. Cellular plasticity of Defa4Cre-expressing Paneth cells in response to Notch activation and intestinal injury.Cell Mol Gastroenterol Hepatol. 2019; 7: 533-554Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 23Yu S. Tong K. Zhao Y. Balasubramanian I. Yap G.S. Ferraris R.P. Bonder E.M. Verzi M.P. Gao N. Paneth cell multipotency induced by Notch activation following injury.Cell Stem Cell. 2018; 23: 46-59.e5Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Dedifferentiation of PCs into a stem-like state is dependent on Notch signaling.21Hayakawa Y. Tsuboi M. Asfaha S. Kinoshita H. Niikura R. Konishi M. Hata M. Oya Y. Kim W. Middelhoff M. Hikiba Y. Higashijima N. Ihara S. Ushiku T. Fukayama M. Tailor Y. Hirata Y. Guha C. Yan K.S. Koike K. Wang T.C. BHLHA15-positive secretory precursor cells can give rise to tumors in intestine and colon in mice.Gastroenterology. 2019; 156: 1066-1081.e16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 22Jones J.C. Brindley C.D. Elder N.H. Myers M.G. Rajala M.W. Dekaney C.M. McNamee E.N. Frey M.R. Shroyer N.F. Dempsey P.J. Cellular plasticity of Defa4Cre-expressing Paneth cells in response to Notch activation and intestinal injury.Cell Mol Gastroenterol Hepatol. 2019; 7: 533-554Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 23Yu S. Tong K. Zhao Y. Balasubramanian I. Yap G.S. Ferraris R.P. Bonder E.M. Verzi M.P. Gao N. Paneth cell multipotency induced by Notch activation following injury.Cell Stem Cell. 2018; 23: 46-59.e5Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar This review will focus on the divergent roles of PCs in homeostasis and intestinal damage. As members of the secretory lineage, PCs require ATOH1, a master secretory regulatory protein, for differentiation and maintenance.24Yang Q. Bermingham N.A. Finegold M.H. Zoghbi H.Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine.Science. 2001; 294: 2155-2158Crossref PubMed Scopus (691) Google Scholar,25VanDussen K.L. Samuelson L.C. Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate.Dev Biol. 2010; 346: 215-223Crossref PubMed Scopus (89) Google Scholar Atoh1 is a downstream target of Wnt/β-catenin signaling. Consistent with the high levels of Wnt/β-catenin signaling in the crypt base, Atoh1 is highly expressed in PCs.26Pinto D. Gregorieff A. Begthel H. Clevers H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium.Genes Dev. 2003; 17: 1709-1713Crossref PubMed Scopus (752) Google Scholar Although they receive comparable levels of Wnt/β-catenin signaling in aISCs, Atoh1 is suppressed by Notch signaling.27VanDussen K.L. Carulli A.J. Keeley T.M. Patel S.R. Puthoff B.J. Magness S.T. Tran I.T. Maillard I. Siebel C. Å Kolterud Grosse A.S. Gumucio D.L. Ernst S.A. Tsai Y.-H. Dempsey P.J. Samuelson L.C. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.Development. 2012; 139: 488-497Crossref PubMed Scopus (331) Google Scholar Notch signaling controls the secretory/absorptive switch in progenitor cells. In addition, other factors direct allocation of secretory progenitors to the PC lineage over other secretory cell fates. GFI1, SPDEF, and SOX9 are known transcription factors that drive transcriptional programs of the PC lineage.28Bastide P. Darido C. Pannequin J. Kist R. 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Scaling factors: transcription factors regulating subcellular domains.BioEssays. 2012; 34: 10-16Crossref PubMed Scopus (42) Google Scholar We have recently shown that PC maturity and maintenance of their secretory capacity are maintained by Mist1 expression.32Dekaney C.M. King S. Sheahan B. Cortes J.E. Mist1 expression is required for Paneth cell maturation.Cell Mol Gastroenterol Hepatol. 2019; 8: 549-560Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Wnt signaling, which activates β-catenin/Tcf transcriptional programs, plays an important role in maintaining PC identity. Secretory progenitors can be directed to the PC lineage by enhancement of β-catenin/Tcf signaling via FGFR3 signaling.33Vidrich A. Buzan J.M. Brodrick B. Ilo C. Bradley L. Fendig K.S. Sturgill T. Cohn S.M. 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Wnt signalling induces maturation of Paneth cells in intestinal crypts.Nat Cell Biol. 2005; 7: 381-386Crossref PubMed Scopus (465) Google Scholar FZD5 interacts with LGR4 together with Wnt molecules to drive β-catenin/Tcf signaling in PCs. Loss of LGR4 produced a more drastic alteration than FZD5 knockout, causing an 85% reduction in PC number.35de Lau W. Barker N. Low T.Y. Koo B.-K. Li V.S.W. Teunissen H. Kujala P. Haegebarth A. Peters P.J. van de Wetering M. Stange D.E. van Es J. Guardavaccaro D. Schasfoort R.B.M. Mohri Y. Nishimori K. Mohammed S. Heck A.J.R. Clevers H. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling.Nature. 2011; 476: 293-297Crossref PubMed Scopus (845) Google Scholar,36Mustata R.C. Van Loy T. Lefort A. Libert F. Strollo S. Vassart G. Garcia M.-I. 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Paneth cell function.The Lancet. 1967; 289: 314-316Abstract Google Scholar However, there was no definitive evidence for their role in the stem cell niche until 2011, when Sato et al7Sato T. van Es J.H. Snippert H.J. Stange D.E. Vries R.G. van den Born M. Barker N. Shroyer N.F. van de Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1507) Google Scholar demonstrated that PCs significantly improved stem cell survival when co-cultured with isolated single aISCs, and that they secreted critical Wnt factors. This article suggested that PCs are sources of Delta-like ligand 4 (DLL4), EGF, and transforming growth factor α, on the basis of transcriptional analysis of PCs compared with ISCs. Others have also demonstrated that PCs are sources of Notch ligands DLL1 and DLL4, binding to Notch receptors Notch1 and Notch2 on ISCs and absorptive progenitors.27VanDussen K.L. Carulli A.J. Keeley T.M. Patel S.R. Puthoff B.J. Magness S.T. Tran I.T. Maillard I. Siebel C. Å Kolterud Grosse A.S. Gumucio D.L. Ernst S.A. Tsai Y.-H. Dempsey P.J. Samuelson L.C. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.Development. 2012; 139: 488-497Crossref PubMed Scopus (331) Google Scholar,41Carulli A.J. Keeley T.M. Demitrack E.S. Chung J. Maillard I. Samuelson L.C. Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration.Dev Biol. 2015; 402: 98-108Crossref PubMed Google Scholar Because of the seminal paper by Sato et al identifying the PC's role in aISC survival in vitro, considerable interest has been directed at understanding the PC-ISC interaction. Wnt/β-catenin signaling is critical for aISC self-renewal and survival. PCs express the canonical Wnt ligands (Figure 1) Wnt3a, Wnt 9b, and Wnt11, which bind to Frizzled receptors on aISCs to drive β-catenin/Tcf signaling.7Sato T. van Es J.H. Snippert H.J. 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Canonical Wnt signaling ameliorates aging of intestinal stem cells.Cell Rep. 2017; 18: 2608-2621Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar and increased secretion of Notum, a Wnt inhibitor.48Pentinmikko N. Iqbal S. Mana M. Andersson S. Cognetta A.B. Suciu R.M. Roper J. Luopajärvi K. Markelin E. Gopalakrishnan S. Smolander O.-P. Naranjo S. Saarinen T. Juuti A. Pietiläinen K. Auvinen P. Ristimäki A. Gupta N. Tammela T. Jacks T. Sabatini D.M. Cravatt B.F. Yilmaz Ö.H. Katajisto P. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium.Nature. 2019; 571: 398-402Crossref PubMed Scopus (49) Google Scholar However, in mice, PCs are dispensable for homeostasis and functionally redundant in vivo, because it has been shown that there are mesenchymal sources of Wnt.49Samuelson L.C. Debate over the identity of an intestinal niche-cell population settled.Nature. 2018; 558: 380-381Crossref PubMed Scopus (3) Google Scholar When subepithelial Wnt support is absent in organoid culture, PC presence or exogenous Wnt supplementation is required.50Durand A. Donahue B. Peignon G. Letourneur F. Cagnard N. Slomianny C. Perret C. Shroyer N.F. Romagnolo B. Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1).Proc Natl Acad Sci. 2012; 109: 8965-8970Crossref PubMed Scopus (0) Google Scholar,51Farin H.F. Van Es J.H. Clevers H. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells.Gastroenterology. 2012; 143: 1518-1529.e7Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Ultimately, PCs are important, although not required, for providing and modulating Wnt/β-catenin signaling within the SI. Notch signaling is essential to maintain stemness, and without it, aISCs differentiate into secretory lineage cells.5Pellegrinet L. Rodilla V. Liu Z. Chen S. Koch U. Espinosa L. Kaestner K.H. Kopan R. Lewis J. Radtke F. Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells.Gastroenterology. 2011; 140: 1230-1240.e7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,52van Es J.H. van Gijn M.E. Riccio O. van den Born M. Vooijs M. Begthel H. Cozijnsen M. Robine S. Winton D.J. Radtke F. Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.Nature. 2005; 435: 959-963Crossref PubMed Scopus (1187) Google Scholar PCs are a major source of Notch ligands (Figure 1); PCs and Notch signaling develop together over the first 2–3 weeks of life in the intestine of post-natal mice.53Schröder N. Gossler A. 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