<i>Hopx</i> expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells

Takeda, Norifumi; Jain, Rajan; LeBoeuf, Matthew; Padmanabhan, Arun; Wang, Qiaohong; Li, Li; Lü, Min; Millar, Sarah E.; Epstein, Jonathan A.

doi:10.1242/dev.093005

Cited by 68 publications

(85 citation statements)

References 66 publications

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“…For example, Hopx is expressed by +4 stem cells in the intestine (19) where niche Bmp signals repress Wnt (28, 36). Recent work by the Fuchs laboratory also suggests that balance between Bmp and Wnt signaling influences the fate of hair follicle cells as they differentiate into various progeny lineages (35) and Hopx may play a role in this process (18). HOPX is a tumor suppressor gene implicated in colorectal and other cancers (37, 38).…”

Section: Discussionmentioning

confidence: 99%

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Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

Jain

Gupta

et al. 2015

Science

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143

148

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Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor.

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Section: Discussionmentioning

confidence: 99%

“…We used a knock-in allele in which Hopx is epitope tagged and GFP is expressed in Hopx + cells (18) to determine that Hopx is expressed in a subset of CPCs at E8.0 and E8.5 in the FHF and SHF, respectively (Fig. 1, A and B).…”

Section: Cardiomyoblasts Are Defined By Hopx Expressionmentioning

confidence: 99%

Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

Jain

Gupta

et al. 2015

Science

Self Cite

143

148

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“…The Sftpc CreERT2 mouse line was a generous gift of Hal Chapman at the University of California at San Francisco and their genotyping and generation have been previously described 34 . Hopx 3FlagGFP mice 35 were a generous gift of Rajan Jain and Jonathan Epstein at the University of Pennsylvania and are available at Jackson Laboratories. The R26R EYFP mice are available at Jackson Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor

Zacharias

Frank

Zepp

et al. 2018

Nature

603

698

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Functional tissue regeneration is required for restoration of normal organ homeostasis after severe injury. While some organs, such as the intestine, harbor active stem cells throughout homeostasis and regeneration1, more quiescent organs like the lung often contain facultative progenitor cells which are recruited after injury to participate in regeneration2,3. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 (AT2) cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome, and functional phenotype with specific responsiveness to Wnt and Fgf signaling. In distinction to other proposed lung progenitor cells, human AEPs (hAEPs) can be directly isolated via expression of the conserved cell surface marker TM4SF1, and hAEPs act as functional human alveolar epithelial progenitor cells in 3D organoids. Together, our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor and a new target for human lung regeneration strategies.

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“…IL-2 −/− mice (33) were bred with Hopx −/− mice and IL-2 +/− heterozygotes were used to produce Hopx −/− IL-2 −/− and Hopx −/− IL-2 +/+ / 2D2 TCR tg Foxp3 RFP and non-TCR tg Foxp3 RFP mice. Hopx Flag-viral2A-GFP reporter mice (34) that faithfully track Hopx expression were first bred on the C57BL/6 background and then crossed with Foxp3 RFP reporter mice (31) and also with 2D2 TCR tg mice (32). Sex and age-matched littermates were used for experiments.…”

Section: Methodsmentioning

confidence: 99%

Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression

Jones

Opejin

Henderson

et al. 2015

The Journal of Immunology

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Dendritic Cells (DCs) can induce peripheral immune tolerance that prevents autoimmune responses. Antigen presentation by peripheral DCs under steady state conditions leads to a conversion of some peripheral CD4+ T cells into Treg cells that require Homeodomain Only Protein (Hopx) to mediate T cell unresponsiveness. However, the roles of these peripheral (p)Treg cells in averting autoimmune responses as well as immunological mechanisms of Hopx remain unknown. Here we report that Hopx+ pTreg cells converted by DCs from Hopxneg T cells are indispensible to sustain tolerance that prevents autoimmune responses directed at self-antigens during experimental acute encephalomyelitis (EAE). Our studies further reveal that Hopx inhibits intrinsic IL-2 expression in pTreg cells after antigenic re-challenge. In the absence of Hopx, increased levels of IL-2 lead to death and decreased numbers of pTreg cells. Therefore formation of Hopx+ pTreg cells represents a crucial pathway of sustained tolerance induced by peripheral DCs and the maintenance of such pTreg cells and tolerance requires functions of Hopx to block intrinsic IL-2 production in pTreg cells.

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Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells

Cited by 68 publications

References 66 publications

Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor

Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression

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