Potent agonists of the Hedgehog signaling pathway

Mesoderm is the developmental precursor to myriad human tissues including bone, heart, and skeletal muscle. Unravelling the molecular events through which these lineages become diversified from one another is integral to developmental biology and understanding changes in cellular fate. To this end, we developed an in vitro system to differentiate human pluripotent stem cells through primitive streak intermediates into paraxial mesoderm and its derivatives (somites, sclerotome, dermomyotome) and separately, into lateral mesoderm and its derivatives (cardiac mesoderm). Whole-population and single-cell analyses of these purified populations of human mesoderm lineages through RNA-seq, ATAC-seq, and high-throughput surface marker screens illustrated how transcriptional changes co-occur with changes in open chromatin and surface marker landscapes throughout human mesoderm development. This molecular atlas will facilitate study of human mesoderm development (which cannot be interrogated in vivo due to restrictions on human embryo studies) and provides a broad resource for the study of gene regulation in development at the single-cell level, knowledge that might one day be exploited for regenerative medicine.

show abstract

“…Media was changed every 24 h for all steps. The small-molecule Hedgehog agonist 21 K 29 was commercially synthesized.…”

Section: Methodsmentioning

confidence: 99%

An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development

et al. 2016

View full text Add to dashboard Cite

show abstract

“…To determine whether increased Hedgehog pathway activity can enhance TRC regeneration within fungiform papillae, we administered the Smoothened agonist SAG21k (30,31) during the 4-wk recovery period (Fig. 6 A and B).…”

Section: Pharmacologic Activation Of Hedgehog Pathway Facilitates Trcmentioning

confidence: 99%

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Mann

Nguyen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

show abstract

“…2C). To further explore pathway activation, we tested the effect of a small-molecule Smoothened agonist, SAG21k (14,15), which generates a 2.8-fold maximal elevation of Gli1 transcript levels in the colon of uninjured FVB mice at a dose of 0.5 mg/kg twice per day (Fig. S2D).…”

Section: Reduction Of Hh Pathway Activity Exacerbates Acute Dss-inducedmentioning

confidence: 99%

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Lee

Rothenberg

Seeley

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4+Foxp3+ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

show abstract

Potent agonists of the Hedgehog signaling pathway

Cited by 23 publications

References 14 publications

An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development

An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Contact Info

Product

Resources

About