Hedgehog: the key to maintaining adult lung repair and regeneration

Sriperumbudur, Amruthansh; Breitzig, Mason; Lockey, Richard F.; Kolliputi, Narasaiah

doi:10.1007/s12079-016-0365-3

Cited by 8 publications

(6 citation statements)

References 9 publications

(19 reference statements)

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“…Gene Set Enrichment Analysis demonstrated distinct immune pathways in lungs obtained from wild-type and TCRδ −/− mice (Figure 1G). Several pathways relevant to tissue development and regeneration were enriched in wild-type lungs, including the epithelial growth factor receptor (EGFR) pathway (Hall et al, 2016; Monticelli et al, 2011; Zaiss et al, 2015) and the hedgehog pathway (Hogan et al, 2014; Sriperumbudur et al, 2017). The absence of γδ T cells was associated with increased inflammatory pathways, including TNF-α, IL-6, and IL-5.…”

Section: Resultsmentioning

confidence: 99%

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

et al. 2018

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Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis.

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Section: Resultsmentioning

confidence: 99%

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

et al. 2018

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“…WNT2B and numerous proteins downstream of active Hedgehog signaling were upregulated, suggesting Wnt and Hedgehog signaling are important in colonoid regeneration. Both pathways have been implicated in organ development and maintenance ( Clevers, 2006 ; Petrova and Joyner, 2014 ), with Hedgehog signaling described as important in regeneration of most organs ( Adolphe, 2004 ; Konstantinou et al., 2016 ; Langiewicz et al., 2016 ; Le et al., 2008 ; Sriperumbudur et al., 2016 ; Trowbridge et al., 2006 ; Wang et al., 2016a , 2016b ). Although recent studies have focused on the crosstalk between Wnt and Hedgehog signaling in cancer progression ( Jiang et al., 2014 ; Regan et al., 2017 ; Song et al., 2015 ), these two pathways also have been implicated in regeneration of bladder epithelia, bone, and adrenal glands ( Day and Yang, 2008 ; Finco et al., 2018 ; Shin et al., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hedgehog and Wnt signaling are essential pathways in development, homeostasis, and regeneration of many organs. Hedgehog signaling is essential in skin wound healing ( Le et al., 2008 ); cardiac ( Wang et al., 2016a ), gastric ( Konstantinou et al., 2016 ), lung ( Sriperumbudur et al., 2016 ), hematopoietic ( Trowbridge et al., 2006 ), and liver regeneration ( Langiewicz et al., 2016 ; Wang et al., 2016b ); as well as epidermal stem cell homeostasis ( Adolphe, 2004 ). In addition, intestinal regeneration in Drosophila is stimulated by active Hedgehog signaling ( Tian et al., 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Epithelial WNT2B and Desert Hedgehog Are Necessary for Human Colonoid Regeneration after Bacterial Cytotoxin Injury

In¹,

Yin²,

Atanga³

et al. 2020

iScience

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Summary Intestinal regeneration and crypt hyperplasia after radiation or pathogen injury relies on Wnt signaling to stimulate stem cell proliferation. Mesenchymal Wnts are essential for homeostasis and regeneration in mice, but the role of epithelial Wnts remains largely uncharacterized. Using the enterohemorrhagic E. coli -secreted cytotoxin EspP to induce injury to human colonoids, we evaluated a simplified, epithelial regeneration model that lacks mesenchymal Wnts. Here, we demonstrate that epithelial-produced WNT2B is upregulated following injury and essential for regeneration. Hedgehog signaling, specifically activation via the ligand Desert Hedgehog (DHH), but not Indian or Sonic Hedgehog, is another driver of regeneration and modulates WNT2B expression. These findings highlight the importance of epithelial WNT2B and DHH in regulating human colonic regeneration after injury.

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“…Non-canonical HH signalling includes three modalities: (i) ligand-dependent/Smo-independent activation; (ii) ligand-dependent/Gli-independent activation; (iii) Gli-only activation [18], [19], [20], [21]. Thus, HH signalling is required in early and postnatal lung development [15,22,23] and orchestrates adult lung repair and regeneration [24,25]. In addition, genome-wide association studies performed in COPD and non-COPD patients identified genetic alterations of HH-linked molecular actors [26], [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD

et al. 2020

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Background: Hedgehog (HH) pathway is constantly under scrutiny in the context of organ development. Lung morphogenesis requires HH signalling which participates thereafter to the pulmonary homeostasis by regulating epithelial cell quiescence and repair. Since epithelial remodelling is a hallmark of Chronic Obstructive Pulmonary Disease (COPD), we investigated whether the main molecular actors of HH pathway participate to airway epithelial cell differentiation and we analysed their alterations in COPD patients. Methods: Sonic HH (Shh) secretion was assessed by ELISA in airway epithelial cell (AEC) air-liquid interface culture supernatants. HH pathway activation was evaluated by RT-qPCR, western blot and immunostaining. Inhibition of HH signalling was achieved upon Shh chelation during epithelial cell differentiation. HH pathway core components localization was investigated in lung tissues from non-COPD and COPD patients. Findings: We demonstrate that progenitors of AEC produced Shh responsible for the activation of HH signalling during the process of differentiation. Preventing the ligand-induced HH activation led to the establishment of a remodelled epithelium with increased number of basal cells and reduced ciliogenesis. Gli2 activating transcription factor was demonstrated as a key-element in the regulation of AEC differentiation. More importantly, Gli2 and Smo were lost in AEC from COPD patients. Interpretation: Our data suggest that HH pathway is crucial for airway epithelial cell differentiation and highlight its role in COPD-associated epithelial remodelling.

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Hedgehog: the key to maintaining adult lung repair and regeneration

Cited by 8 publications

References 9 publications

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

Epithelial WNT2B and Desert Hedgehog Are Necessary for Human Colonoid Regeneration after Bacterial Cytotoxin Injury

Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD

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