Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology

Abstract

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.

Glioblastoma is spatially organized by neurodevelopmental programs and a glial-like wound healing response

“…For flow cytometry analyses, frozen cell suspensions were washed in 10 ml RPMI-1640 containing 10% HI FBS and intracellular staining was performed as previously described 80 . Briefly, cells were first stained for 20 min at RT with extracellular antibodies in the staining mix containing FACS buffer (dPBS (Sigma) with 2% HI FBS (Gibco) and 0.4% 0.5M EDTA (Invitrogen) added), 1:5 BD Horizon Brilliant Stain buffer (BD Biosciences), and 1:25 FcR blocking reagent (Miltenyi), followed by fixation using BD FixPerm buffer (BD Biosciences) for 30 min at RT, and stained with intracellular antibodies in BD Perm/Wash buffer (BD Biosciences) for 20 min at RT.…”

Identification and characterization of stromal-like cells with CD207+/low CD1a+/low phenotype derived from histiocytic lesions – a perspective in vitro model for drug testing

“…Deep profiling of LCH cell heterogeneity using single cell RNA-seq technology also indicated on significant impact of microenvironmental factors on the phenotype and gene expression profile of LCH cells [ 29 , 30 ]. The LCH heterogeneity may arise from developmental processes such as cellular differentiation, de-differentiation, or transdifferentiation [ 29 ]. The fact that that LCH exhibits key characteristics common to both cancers and immune disorders, positioning it as a uniquely valuable model for biomedical studies.…”

Possible correlated signaling pathways with chronic urate nephropathy: A review

“…MAPK plays an important role in signal transduction. MAPK can be stimulated by a variety of extracellular stimuli (growth factors, [96] cytokines, [97] lipotoxicity, [98] rate threshold [99] ) and activate serine-threonine protein kinases to transduce cell [101] p38, [102] JNK, [103] ERK5 [104] ) through protein factors (RAS, [105] MAP3K, [106] MAP2K, [107] MAPK [108] ) which in turn regulate cell proliferation, [109] differentiation, [110] inflammation-mediated [111] and apoptosis. [112] The pathological basis of HN is that excessive deposition of urate induces phenotypic changes in renal tubular epithelial cell injury.…”

“…MAPK can be stimulated by a variety of extracellular stimuli (growth factors, [96] cytokines, [97] lipotoxicity, [98] rate threshold [99] ) and activate serine-threonine protein kinases to transduce cell surface signals into the nucleus. [100] The key to the intracellular phosphorylation cascade is the activation of the MAPK signaling pathway, which receives extracellular signals to act on membrane receptors and activates downstream target gene transcription factors (ERK, [101] p38, [102] JNK, [103] ERK5 [104] ) through protein factors (RAS, [105] MAP3K, [106] MAP2K, [107] MAPK [108] ) which in turn regulate cell proliferation, [109] differentiation, [110] inflammation-mediated [111] and apoptosis. [112] The pathological basis of HN is that excessive deposition of urate induces phenotypic changes in renal tubular epithelial cell injury.…”