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The stem cell niche is a complex local signaling microenvironment that regulates stem cell activity for tissue and organ maintenance and regeneration. As well as responding locally, during puberty, the mammary gland stem cell niche also responds to systemic hormonal signals. Zhao et al. have found that Gli2, a transcriptional effector of Hedgehog signaling, coordinates the niche-signaling program and activates expression of receptors for the mammatrophic hormones estrogen and growth hormone throughout the mammary gland (see the Perspective by Robertson). Disease may result not only from stem cell defects, but also from dysregulation of the microenvironment. Science , this issue p. eaal3485 ; see also p. 250 The GLI2 transcription factor regulates stromal cell expression of signals controlling breast epithelial stem cell activity. The stem cell niche is a complex local signaling microenvironment that sustains stem cell activity during organ maintenanceorgan maintenance and regeneration. The mammary gland niche must support its associated stem cells while also responding to systemic hormonal regulation that triggers pubertal changes. We find that Gli2 , the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone. Whereas prior studies implicate stem cell defects in human disease, this work shows that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency.

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

Magnetars and central compact objects (CCOs) are subgroups of neutron stars that show a number of properties distinguished from canonical radio pulsars. We performed radio observations of three magnetars, SGR 0418+5729, 1E 2259+586, and 4U 0142+61, and a CCO, PSR J1852+0040, with the Five-hundred-meter Aperture Spherical radio Telescope at 1.25 GHz, aiming to search for radio pulsations in their quiescent states. During two observation epochs, no radio pulses have been detected toward any target above a significance of signal-to-noise ratio = 7 from either the direct folding or blind search. We provided the most stringent upper limit of radio flux (≲2–4 μJy) for the magnetars and the CCO. For the magnetars with long periods, the real upper limits are likely 1 order of magnitude larger due to the red noise. The deep radio observations suggest that these magnetars and the CCO are indeed radio-quiet sources or unfavorably beamed.

Fast radio bursts (FRBs) are energetic millisecond phenomena in the radio band. Polarimetric studies of repeating FRBs indicate that many of these sources occupy extreme and complex magnetoionized environments. Recently, a frequency-dependent depolarization has been discovered in several repeating FRBs. However, the temporal evolution of polarization properties is limited by the burst rate and observational cadence of telescopes. In this Letter, the temporal evolution of depolarization in repeating FRB 20201124A is explored. Using the simultaneous variation of rotation measure and dispersion measure, we also measure the strength of a magnetic field parallel to the line of sight. The strength ranges from a few μG to 103 μG. In addition, we find that the evolution of depolarization and magnetic field traces the evolution of rotation measure. Our result supports that the variation of depolarization, rotation measure, and the magnetic field are determined by the same complex magnetoionized screen surrounding the FRB source. The derived properties of the screen are consistent with the wind and the decretion disk of a massive star.

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.

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.

The evolutionary appearance of p53 protein probably preceded its role in tumor suppression, suggesting that there may be unappreciated functions for this protein. Using genetic reporters as proxies to follow in vivo activation of the p53 network in Drosophila, we discovered that the process of meiotic recombination instigates programmed activation of p53 in the germ line. Specifically, double-stranded breaks in DNA generated by the topoisomerase Spoil provoked functional p53 activity, which was prolonged in cells defective for meiotic DNA repair. This intrinsic stimulus for the p53 regulatory network is highly conserved because Spoil-dependent activation of p53 also occurs in mice. Our findings establish a physiological role for p53 in meiosis and suggest that tumor-suppressive functions may have been co-opted from primordial activities linked to recombination.

Oncogenic stress provokes tumor suppression by p53 but the extent to which this regulatory axis is conserved remains unknown. Using a biosensor to visualize p53 action, we find that Drosophila p53 is selectively active in gonadal stem cells after exposure to stressors that destabilize the genome. Similar p53 activity occurred in hyperplastic growths that were triggered either by the RasV12 oncoprotein or by failed differentiation programs. In a model of transient sterility, p53 was required for the recovery of fertility after stress, and entry into the cell cycle was delayed in p53- stem cells. Together, these observations establish that the stem cell compartment of the Drosophila germline is selectively licensed for stress-induced activation of the p53 regulatory network. Furthermore, the findings uncover ancestral links between p53 and aberrant proliferation that are independent of DNA breaks and predate evolution of the ARF/Mdm2 axis. The most common genetic change seen in cancer patients produces a faulty version of the p53 protein, which normally restricts tissue growth. This change promotes cancer because cells can now divide faster and fail to die when they should. Much remains to be learned about how p53 functions to restrain growth. As p53 is found in primitive organisms, and cancer is unlikely to have significantly influenced evolution, suppressing tumor formation was almost certainly not the original function of this gene. Furthermore, p53 works in a different way compared to many other tumour suppressors. Therefore, prevention of cancer is likely to have evolved as a side effect derived from more ancient functions. Recently, a link between p53 and stem cells has been uncovered. Stem cells are special because they can develop into many different types of cells, and they are crucial for the growth and repair of tissues. To form a particular type of cell, the stem cell divides to create two daughter cells. Commonly, one daughter cell stays in the stem state, whereas the other becomes a particular type of cell, such as a nerve cell or muscle cell. Because of this special property, scientists hypothesize that stem cells have special mechanisms to protect them from DNA damage that might partially depend on p53. This would prevent the spread of damaged genomes that would otherwise occur among daughter cells. To learn more about how p53 influences stem cells, Wylie, Lu et al. monitored its activity in the gonads of fruit flies, which are a powerful genetic model. They found that damaging DNA activates p53 in stem cells and their daughter cells, but not in other types of cells that have been damaged. In addition, p53 is activated by the uncontrolled growth and division of stem cells in the gonad, even when DNA is not damaged. This is unexpected since molecules linking inappropriate growth to p53 were thought to be present only in mammals. Therefore, it appears that the tumor-suppressing behavior of p53 in mammals was adapted from its more ancient ability to regulate stem cell growth—an ability that evolved before organisms divided into vertebrates and invertebrates.

Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([ 18 F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [ 18 F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [ 18 F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [ 18 F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [ 18 F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [ 18 F]FDG uptake could potentially obfuscate the interpretation of [ 18 F]FDG-PET scans in patients who have recently undergone radiation therapy.

Activation of the Hedgehog pathwaymay have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental, and agents amenable to tissue targeting for therapeutic application have been lacking. We have developed an agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1 (PTCH1). This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 “switch helix,” as revealed by our cryogenic electron microscopy structure. Nanobody-binding likely traps Patched in one stage of its transport cycle, thus preventing substrate movement through the Patched1 sterol conduit. Unlike the native Hedgehog ligand, this nanobody does not require lipid modifications for its activity, facilitating mechanistic studies of Hedgehog pathway activation and the engineering of pathway activating agents for therapeutic use. Our conformation-selective nanobody approach may be generally applicable to the study of other PTCH1 homologs.