bims-mepmim 2024-08-25 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024‒08‒25
23 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.
Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells.
Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.
NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.
PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.
Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis.
The role of brown adipose tissue in branched-chain amino acid clearance in people.
High-fat feeding drives the intestinal production and assembly of C16:0 ceramides in chylomicrons.
Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors.
A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.
Dynamic regulation of tissue fluidity controls skin repair during wound healing.
MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant ischemia-reperfusion injury.
LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.
Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.
Cancer tissue of origin constrains the growth and metabolism of metastases.
Cell fate simulation reveals cancer cell features in the tumor microenvironment.
Investigation of MSC potency metrics via integration of imaging modalities with lipidomic characterization.

Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.

  To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux

DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
Sci Immunol. 2024 Aug 23. 9(98): eadn2717

PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.

Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho.

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.

DOI: https://doi.org/10.1126/sciimmunol.adn2717
Mol Cell. 2024 Aug 06. pii: S1097-2765(24)00619-1. [Epub ahead of print]

Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.

Zhenxi Zhang, Yanting Yang, Yang Chen, Jingyu Su, Wenjing Du.

  The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.

Keywords:  CD8(+) T cell; DAPK1; antitumor immunity; fumarate; malic enzyme 2; metabolite sensing

DOI:  https://doi.org/10.1016/j.molcel.2024.07.021
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2405746121

Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.

Souradipta Ganguly, Sara Brin Rosenthal, Kei Ishizuka, Ty D Troutman, Theresa V Rohm, Naser Khader, German Aleman-Muench, Yasuyo Sano, Sebastiano Archilei, Pejman Soroosh, Jerrold M Olefsky, Ariel E Feldstein, Tatiana Kisseleva, Rohit Loomba, Christopher K Glass, David A Brenner, Debanjan Dhar.

  While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.

Keywords:  Trem2; fibrosis; lipid associated macrophages (LAM); macrophage; steatohepatitis

DOI:  https://doi.org/10.1073/pnas.2405746121
Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632

Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.

  Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Keywords:  CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex

DOI:  https://doi.org/10.1016/j.celrep.2024.114632
J Biol Chem. 2024 Aug 14. pii: S0021-9258(24)02179-3. [Epub ahead of print] 107678

FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells.

Shuko Miyahara, Mai Ohuchi, Miyuki Nomura, Eifumi Hashimoto, Tomoyoshi Soga, Rintaro Saito, Kayoko Hayashi, Taku Sato, Masatoshi Saito, Yoji Yamashita, Muneaki Shimada, Nobuo Yaegashi, Hidekazu Yamada, Nobuhiro Tanuma.

  Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global down-regulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53-deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids (PLs). Our results suggest that p53 status and PL homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.

Keywords:  DNA damage response; cancer biology; cell death; cellular senescence; gene knockout; iron metabolism; iron-sulfur protein; ovarian cancer; p53; reactive oxygen species (ROS); redox regulation; tumor metabolism

DOI:  https://doi.org/10.1016/j.jbc.2024.107678
Immunity. 2024 Aug 07. pii: S1074-7613(24)00368-6. [Epub ahead of print]

Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.

Emile Wogram, Felix Sümpelmann, Wentao Dong, Eshaan Rawat, Inés Fernández Maestre, Dongdong Fu, Brandyn Braswell, Andrew Khalil, Joerg M Buescher, Gerhard Mittler, Georg H H Borner, Andreas Vlachos, Stefan Tholen, Oliver Schilling, George W Bell, Angelika S Rambold, Asifa Akhtar, Oliver Schnell, Jürgen Beck, Monther Abu-Remaileh, Marco Prinz, Rudolf Jaenisch.

  Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis-and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions. Here, we developed a method for rapid isolation of pure and intact phagosomes from human pluripotent stem cell-derived microglia under various in vitro conditions, and from human brain biopsies, for unbiased multiomic analysis. Phagosome profiling revealed that microglial phagosomes were equipped to sense minute changes in their environment and were highly dynamic. We detected proteins involved in synapse homeostasis, or implicated in brain pathologies, and identified the phagosome as the site where quinolinic acid was stored and metabolized for de novo nicotinamide adenine dinucleotide (NAD+) generation in the cytoplasm. Our findings highlight the central role of phagosomes in microglial functioning in the healthy and diseased brain.

Keywords:  glioblastoma; human pluripotent stem cells; metabolomics; microglia; organelle; phagocytosis; phagosome; proteomics; quinolinic acid; synaptic pruning

DOI:  https://doi.org/10.1016/j.immuni.2024.07.019
JCI Insight. 2024 Jul 18. pii: e177152. [Epub ahead of print]9(16):

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.

Caroline E Perry, Sarah M Halawani, Sarmistha Mukherjee, Lucie V Ngaba, Melissa Lieu, Won Dong Lee, James G Davis, Gabriel K Adzika, Alyssa N Bebenek, Daniel D Bazianos, Beishan Chen, Elizabeth Mercado-Ayon, Liam P Flatley, Arjun P Suryawanshi, Isabelle Ho, Joshua D Rabinowitz, Suraj D Serai, David M Biko, Jaclyn Tamaroff, Anna DeDio, Kristin Wade, Kimberly Y Lin, David J Livingston, Shana E McCormack, David R Lynch, Joseph A Baur.

  Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

Keywords:  Cardiology; Metabolism; Mitochondria; Neurological disorders

DOI:  https://doi.org/10.1172/jci.insight.177152
EMBO J. 2024 Aug 19.

PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.

Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu.

  Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.

Keywords:  BATokine; Fibrosis; MASH; Obesity; PCPE-1

DOI:  https://doi.org/10.1038/s44318-024-00196-0
Sci Adv. 2024 Aug 23. 10(34): eadi6286

Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis.

Manasa Chanduri, Abhishek Kumar, Dar Weiss, Nir Emuna, Igor Barsukov, Miusi Shi, Keiichiro Tanaka, Xinzhe Wang, Amit Datye, Jean Kanyo, Florine Collin, TuKiet Lam, Udo D Schwarz, Suxia Bai, Timothy Nottoli, Benjamin T Goult, Jay D Humphrey, Martin A Schwartz.

Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained by resident cells. Despite its broad importance to biology and medicine, tissue mechanical homeostasis remains poorly understood. To explore cell-mediated control of tissue stiffness, we developed mutations in the mechanosensitive protein talin 1 to alter cellular sensing of ECM. Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 increased cell spreading and tension exertion on compliant substrates. These mutations promote binding of the ARP2/3 complex subunit ARPC5L, which mediates the change in substrate stiffness sensing. Ascending aortas from mice bearing these mutations showed less fibrillar collagen, reduced axial stiffness, and lower rupture pressure. Together, these results demonstrate that cellular stiffness sensing contributes to ECM mechanics, directly supporting the mechanical homeostasis hypothesis and identifying a mechanosensitive interaction within talin that contributes to this mechanism.

DOI: https://doi.org/10.1126/sciadv.adi6286
iScience. 2024 Aug 16. 27(8): 110559

The role of brown adipose tissue in branched-chain amino acid clearance in people.

Yasser G Abdelhafez, Guobao Wang, Siqi Li, Vanessa Pellegrinelli, Abhijit J Chaudhari, Anthony Ramirez, Fatma Sen, Antonio Vidal-Puig, Labros S Sidossis, Samuel Klein, Ramsey D Badawi, Maria Chondronikola.

  Brown adipose tissue (BAT) in rodents appears to be an important tissue for the clearance of plasma branched-chain amino acids (BCAAs) contributing to improved metabolic health. However, the role of human BAT in plasma BCAA clearance is poorly understood. Here, we evaluate patients with prostate cancer who underwent positron emission tomography-computed tomography imaging after an injection of 18F-fluciclovine (L-leucine analog). Supraclavicular adipose tissue (AT; primary location of human BAT) has a higher net uptake rate for 18F-fluciclovine compared to subcutaneous abdominal and upper chest AT. Supraclavicular AT 18F-fluciclovine net uptake rate is lower in patients with obesity and type 2 diabetes. Finally, the expression of genes involved in BCAA catabolism is higher in the supraclavicular AT of healthy people with high BAT volume compared to those with low BAT volume. These findings support the notion that BAT can potentially function as a metabolic sink for plasma BCAA clearance in people.

Keywords:  Cancer; Human genetics; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2024.110559
Sci Adv. 2024 Aug 23. 10(34): eadp2254

High-fat feeding drives the intestinal production and assembly of C16:0 ceramides in chylomicrons.

Michael Sm Mah, Enyuan Cao, Dovile Anderson, Alistair Escott, Surafel Tegegne, Gracia Gracia, Joel Schmitz, Susanne Brodesser, Colby Zaph, Darren J Creek, Jiwon Hong, John A Windsor, Anthony Rj Phillips, Natalie L Trevaskis, Mark A Febbraio, Sarah M Turpin-Nolan.

Consumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system. A lipidomic screen of intestinal-derived chylomicrons identified a diverse range of fatty acid, sphingolipid, and glycerolipid species that have not been previously detected in chylomicrons, including the metabolically deleterious C16:0 ceramide that increased in response to high-fat feeding in rats and human high-lipid meal replacement enteral feeding. In conclusion, high-fat feeding increases the export of intestinal-derived C16:0 ceramide in chylomicrons, identifying a potentially unknown mechanism through which ceramides are transported systemically to contribute to metabolic dysfunction.

DOI: https://doi.org/10.1126/sciadv.adp2254
Nature. 2024 Aug 21.

Stem cells tightly regulate dead cell clearance to maintain tissue fitness.

Katherine S Stewart, Merve Deniz Abdusselamoglu, Matthew T Tierney, Anita Gola, Yun Ha Hur, Kevin A U Gonzales, Shaopeng Yuan, Alain R Bonny, Yihao Yang, Nicole R Infarinato, Christopher J Cowley, John M Levorse, Hilda Amalia Pasolli, Sourav Ghosh, Carla V Rothlin, Elaine Fuchs.

Billions of cells are eliminated daily from our bodies1-4. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.

DOI: https://doi.org/10.1038/s41586-024-07855-6
Nat Commun. 2024 Aug 21. 15(1): 7173

Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.

Laurent L'homme, Benan Pelin Sermikli, Joel T Haas, Sébastien Fleury, Sandrine Quemener, Valentine Guinot, Emelie Barreby, Nathalie Esser, Robert Caiazzo, Hélène Verkindt, Benjamin Legendre, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels, David Dombrowicz.

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

DOI: https://doi.org/10.1038/s41467-024-51078-2
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2406748121

Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors.

Ankit Dahal, Yeonsun Hong, Jocelyn S Mathew, Adam Geber, Sarah Eckl, Stephanie Renner, Cooper J Sailer, Allison T Ryan, Sana Mir, Kihong Lim, David C Linehan, Scott A Gerber, Minsoo Kim.

  Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.

Keywords:  Cancer; MDSC; myeloid cells; neutrophil; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2406748121
Cell Rep. 2024 Aug 17. pii: S2211-1247(24)00983-5. [Epub ahead of print]43(8): 114633

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.

Jia-Hao Zheng, Yu-Heng Zhu, Jian Yang, Pei-Xuan Ji, Rui-Kang Zhao, Zong-Hao Duan, Hong-Fei Yao, Qin-Yuan Jia, Yi-Fan Yin, Li-Peng Hu, Qing Li, Shu-Heng Jiang, Yan-Miao Huo, Wei Liu, Yong-Wei Sun, De-Jun Liu.

  Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

Keywords:  CP: Cancer; CP: Metabolism; chloride intracellular channel 1; extracellular matrix stiffness; pancreatic ductal adenocarcinoma; the Warburg effect

DOI:  https://doi.org/10.1016/j.celrep.2024.114633
Cell. 2024 Aug 11. pii: S0092-8674(24)00825-0. [Epub ahead of print]

Dynamic regulation of tissue fluidity controls skin repair during wound healing.

Rahul M Sarate, Joel Hochstetter, Manon Valet, Adrien Hallou, Yura Song, Nordin Bansaccal, Melanie Ligare, Mariaceleste Aragona, Dan Engelman, Anaïs Bauduin, Otger Campàs, Benjamin D Simons, Cedric Blanpain.

  During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.

Keywords:  AP1 transcription factor; Voronoi model; intravital; lineage ablation; regenerative state; skin; stem cells; tissue fluidity; tissue repair; wound healing

DOI:  https://doi.org/10.1016/j.cell.2024.07.031
JCI Insight. 2024 Aug 22. pii: e179876. [Epub ahead of print]

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant ischemia-reperfusion injury.

Victoria Leroy, Denny Joseph Manual Kollareth, Zhenxiao Tu, Jeff Arni C Valisno, Makena Woolet-Stockton, Biplab K Saha, Amir M Emtiazjoo, Mindaugas Rackauskas, Lyle L Moldawer, Philip A Efron, Guoshuai Cai, Carl Atkinson, Gilbert R Upchurch, Ashish K Sharma.

  Lung transplantation (LTx) outcomes are impeded by ischemia-reperfusion injury (IRI) and subsequent chronic lung allograft dysfunction (CLAD). We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and bronchoalveolar lavage (BAL) from post-LTx patients were analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), Cebpb-/- (MDSC-deficient), Mertk-/- or MerTK-CR (cleavage resistant) mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients was observed compared to healthy subjects. In the murine IRI model, significant increase in M-MDSCs, MerTK expression, efferocytosis and attenuation of lung dysfunction was observed in WT mice during injury resolution that was absent in Cebpb-/- and Mertk-/- mice. Adoptive transfer of M-MDSCs in Cebpb-/- mice significantly attenuated lung dysfunction and inflammation. Additionally, in a murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can substantially contribute to the resolution of post-LTx IRI.

Keywords:  Immunology; Innate immunity; Monocytes; Surgery; Transplantation

DOI:  https://doi.org/10.1172/jci.insight.179876
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2405845121

LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.

Juan Wang, Jing Wang, Jiuchang Zhong, Hongbin Liu, Weiming Li, Mulei Chen, Li Xu, Wenbin Zhang, Ze Zhang, Zhizhong Wei, Jia Guo, Xinyu Wang, Jianhua Sui, Xingpeng Liu, Sitao Zhang, Xiaodong Wang.

  Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.

Keywords:  LRG1; atherosclerosis; inflammation; macrophage

DOI:  https://doi.org/10.1073/pnas.2405845121
Elife. 2024 Aug 20. pii: RP91757. [Epub ahead of print]12

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Amber R Philp, Carolina R Reyes, Josselyne Mansilla, Amar Sharma, Chao Zhao, Carlos Valenzuela-Krugmann, Khalil S Rawji, Ginez A Gonzalez Martinez, Penelope Dimas, Bryan Hinrichsen, César Ulloa-Leal, Amie K Waller, Diana M Bessa de Sousa, Maite A Castro, Ludwig Aigner, Pamela Ehrenfeld, Maria Elena Silva, Ilias Kazanis, Cedric Ghevaert, Robin J M Franklin, Francisco J Rivera.

  Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Keywords:  human; mouse; multiple sclerosis; neuroscience; oligodendrocyte progenitor cells; platelets; rat; regenerative medicine; remyelination; stem cells

DOI:  https://doi.org/10.7554/eLife.91757
Nat Metab. 2024 Aug 19.

Cancer tissue of origin constrains the growth and metabolism of metastases.

Sharanya Sivanand, Yetis Gultekin, Peter S Winter, Sidney Y Vermeulen, Konstantine M Tchourine, Keene L Abbott, Laura V Danai, Florian Gourgue, Brian T Do, Kayla Crowder, Tenzin Kunchok, Allison N Lau, Alicia M Darnell, Alexandria Jefferson, Satoru Morita, Dan G Duda, Andrew J Aguirre, Brian M Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J Irvine, Omer H Yilmaz, Caroline A Lewis, Dennis Vitkup, Alex K Shalek, Matthew G Vander Heiden.

Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.

DOI: https://doi.org/10.1038/s42255-024-01105-9
J Biol Chem. 2024 Aug 20. pii: S0021-9258(24)02198-7. [Epub ahead of print] 107697

Cell fate simulation reveals cancer cell features in the tumor microenvironment.

Sachiko Sato, Ann Rancourt, Masahiko S Satoh.

  To elucidate the dynamic evolution of cancer cell characteristics within the tumor microenvironment (TME), we developed an integrative approach combining single-cell tracking, cell fate simulation, and three-dimensional (3D) TME modeling. We began our investigation by analyzing the spatiotemporal behavior of individual cancer cells in cultured pancreatic (MiaPaCa2) and cervical (HeLa) cancer cell lines, with a focus on the α2-6 sialic acid (α2-6Sia) modification on glycans, which is associated with cell stemness. Our findings revealed that MiaPaCa2 cells exhibited significantly higher levels of α2-6Sia modification, correlating with enhanced reproductive capabilities, whereas HeLa cells showed less prevalence of this modification. To accommodate the in vivo variability of α2-6Sia levels, we employed a cell fate simulation algorithm that digitally generates cell populations based on our observed data while varying the level of sialylation, thereby simulating cell growth patterns. Subsequently, we performed a 3D TME simulation with these deduced cell populations, considering the microenvironment that could impact cancer cell growth. Immune cell landscape information derived from 193 cervical and 172 pancreatic cancer cases was used to estimate the degree of the positive or negative impact. Our analysis suggests that the deduced cells generated based on the characteristics of MiaPaCa2 cells are less influenced by the immune cell landscape within the TME compared to those of HeLa cells, highlighting that the fate of cancer cells is shaped by both the surrounding immune landscape and the intrinsic characteristics of the cancer cells.

Keywords:  3-dimensional tumor microenvironment simulation; Sambucus nigra lectin; Single-cell tracking; cancer cell heterogeneity; cancer cell lines; cell fate simulation; cervical cancer; live cell imaging; pancreatic cancer; stemness; tumor microenvironment; α2-6 sialic acid modification on glycans

DOI:  https://doi.org/10.1016/j.jbc.2024.107697
Cell Rep. 2024 Aug 15. pii: S2211-1247(24)00908-2. [Epub ahead of print]43(8): 114579

Investigation of MSC potency metrics via integration of imaging modalities with lipidomic characterization.

Priyanka Priyadarshani, Alexandria Van Grouw, Adrian Ross Liversage, Kejie Rui, Arina Nikitina, Kayvan Forouhesh Tehrani, Bhavay Aggarwal, Steven L Stice, Saurabh Sinha, Melissa L Kemp, Facundo M Fernández, Luke J Mortensen.

  Mesenchymal stem/stromal cell (MSC) therapies have had limited success so far in clinical trials due in part to heterogeneity in immune-responsive phenotypes. Therefore, techniques to characterize these properties of MSCs are needed during biomanufacturing. Imaging cell shape, or morphology, has been found to be associated with MSC immune responsivity-but a direct relationship between single-cell morphology and function has not been established. We used label-free differential phase contrast imaging and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to evaluate single-cell morphology and explore relationships with lipid metabolic immune response. In interferon gamma (IFN-γ)-stimulated MSCs, we found higher lipid abundances from the ceramide-1-phosphate (C1P), phosphatidylcholine (PC), LysoPC, and triglyceride (TAG) families that are involved in cell immune function. Furthermore, we identified differences in lipid signatures in morphologically defined MSC subpopulations. The use of single-cell optical imaging coupled with single-cell spatial lipidomics could assist in optimizing the MSC production process and improve mechanistic understanding of manufacturing process effects on MSC immune activity and heterogeneity.

Keywords:  CP: Immunology; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114579