A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis.

Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis.

Regulation of adipocyte dedifferentiation at the skin wound edge.

Adipocytes have diverse roles in energy storage and metabolism, inflammation, and tissue repair. Mature adipocytes have been assumed to be terminally differentiated cells. However, recent evidence suggests that adipocytes retain substantial phenotypic plasticity, with potential to dedifferentiate into fibroblast-like cells under physiological and pathological conditions.

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves.

Background: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery.

Plap-1 lineage tracing and single-cell transcriptomics reveal cellular dynamics in the periodontal ligament.

Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined.

Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing.

Fibroblasts differentiate into myofibroblasts by acquiring new contractile function. This is important for tissue repair, but it also contributes to organ fibrosis. Platelet-derived growth factor (PDGF) promotes tissue repair and fibrosis, but the relationship between PDGF and myofibroblasts is unclear.

Skeletal stem cell fate defects caused by Pdgfrb activating mutation.

Autosomal dominant PDGFRβ gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFRβ exhibit colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with SSC-derived polyclonal colonies demonstrates alterations in osteogenic and chondrogenic precursors caused by PDGFRβD849V.

Sweet Dre-ams about intersectional genetics.

Specific cell targeting with one site-specific recombinase is challenging. In this issue of Cell Stem Cell, Han et al. (2021) released a collection of Dre drivers and demonstrate how two recombinases can be combined to improve the cell specificity of lineage tracing and gene inactivation in mice.

The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1 hematoendothelial progenitors.

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1 hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcan lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis.

Mosaic Mutant Analysis Identifies PDGFRα/PDGFRβ as Negative Regulators of Adipogenesis.

Adipocyte progenitors (APs) express platelet-derived growth factor receptors (PDGFRs), PDGFRα and PDGFRβ. Elevated PDGFRα signaling inhibits adipogenesis and promotes fibrosis; however, the function of PDGFRs in APs remains unclear. We combined lineage tracing and functional analyses in a sequential dual-recombinase approach that creates mosaic Pdgfr mutant cells by Cre/lox recombination with a linked Flp/frt reporter to track individual cell fates.

Fibroblast-specific Stat1 deletion enhances the myofibroblast phenotype during tissue repair.

Signal transducer and activator of transcription 1 (Stat1) is a ubiquitously expressed latent transcription factor that is activated by many cytokines and growth factors. Global Stat1 knockout mice are prone to chemical-induced lung and liver fibrosis, suggesting roles for Stat1 in tissue repair. However, the importance of Stat1 in fibroblast-mediated and vascular smooth muscle cell (VSMC)-mediated injury response has not been directly evaluated in vivo.

Dysregulated mesenchymal PDGFR-β drives kidney fibrosis.

Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells. To study the consequences of PDGFR-β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts.

Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling.

Wnt/β-catenin signaling is necessary for lymphatic vascular development. Oscillatory shear stress (OSS) enhances Wnt/β-catenin signaling in cultured lymphatic endothelial cells (LECs) to induce expression of the lymphedema-associated transcription factors GATA2 and FOXC2. However, the mechanisms by which OSS regulates Wnt/β-catenin signaling and GATA2 and FOXC2 expression are unknown.

STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation.

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis.

Adipose tissue is distributed in depots throughout the body with specialized roles in energy storage and thermogenesis. PDGFRα is a marker of adipocyte precursors, and increased PDGFRα activity causes adipose tissue fibrosis in adult mice. However, the function of PDGFRα during adipose tissue organogenesis is unknown.

Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway.

Pigment epithelium-derived factor (PEDF) expression is downregulated in the kidneys of diabetic rats, and delivery of PEDF suppressed renal fibrotic factors in these animals. PEDF has multiple functions including anti-angiogenic, anti-inflammatory and antifibrotic activities. Since the mechanism underlying its antifibrotic effect remains unclear, we studied this in several murine models of renal disease.

Detrimental effects of duplicate reads and low complexity regions on RNA- and ChIP-seq data.

Background: Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments.

PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis.

Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in the context of atherosclerosis. Here we present a new mouse model of atherosclerosis with an activating mutation in PDGFRβ.

PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity.

Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis.

Double minute amplification of mutant PDGF receptor α in a mouse glioma model.

In primary brain tumors, oncogenes are frequently amplified and maintained on extrachromosomal DNA as double minutes (DM), but the underlying mechanisms remain poorly understood. We have generated a mouse model of malignant glioma based on knock-in of a mutant PDGF receptor α (PDGFRα) that is expressed in oligodendrocyte precursor cells (OPCs) after activation by a Cre recombinase. In the tumor suppressor INK4/Arf(-/-) background, mutant animals frequently developed brain tumors resembling anaplastic human gliomas (WHO grade III).

Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities.

Fibrosis is the principal characteristic of the autoimmune disease known as scleroderma or systemic sclerosis (SSc). Studies published within the last three years suggest central involvement of platelet-derived growth factors (PDGFs) in SSc-associated fibrosis. PDGFs may also be involved in SSc-associated autoimmunity and vasculopathy.

Radial construction of an arterial wall.

Some of the most serious diseases involve altered size and structure of the arterial wall. Elucidating how arterial walls are built could aid understanding of these diseases, but little is known about how concentric layers of muscle cells and the outer adventitial layer are assembled and patterned around endothelial tubes. Using histochemical, clonal, and genetic analysis in mice, here we show that the pulmonary artery wall is constructed radially, from the inside out, by two separate but coordinated processes.

Asymmetric requirement of surface epithelial β-catenin during the upper and lower jaw development.

Background: Intercellular communication between epithelial and mesenchymal cells is central to mammalian craniofacial development. β-catenin is the gateway of canonical Wnt signaling, one of the major evolutionarily conserved cell-cell communication pathways in metazoa. In this study, we report an unexpected stage- and tissue-specific function of β-catenin during mammalian jaw development.

PDGFRβ signaling regulates mural cell plasticity and inhibits fat development.

Mural cells (pericytes and vascular smooth muscle cells) provide trophic and structural support to blood vessels. Vascular smooth muscle cells alternate between a synthetic/proliferative state and a differentiated/contractile state, but the dynamic states of pericytes are poorly understood. To explore the cues that regulate mural cell differentiation and homeostasis, we have generated conditional knockin mice with activating mutations at the PDGFRβ locus.

Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis.

PDGF signaling regulates the development of mesenchymal cell types in the embryo and in the adult, but the role of receptor activation in tissue homeostasis has not been investigated. We have generated conditional knockin mice with mutations in PDGFRalpha that drive increased kinase activity under the control of the endogenous PDGFRalpha promoter. In embryos, increased PDGFRalpha signaling leads to hyperplasia of stromal fibroblasts, which disturbs normal smooth muscle tissue in radially patterned organs.

Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination.

While the biological roles of canonical Wnt/beta-catenin signaling in development and disease are well documented, understanding the molecular logic underlying the functionally distinct nuclear transcriptional programs mediating the diverse functions of beta-catenin remains a major challenge. Here, we report an unexpected strategy for beta-catenin-dependent regulation of cell-lineage determination based on interactions between beta-catenin and a specific homeodomain factor, Prop1, rather than Lef/Tcfs. beta-catenin acts as a binary switch to simultaneously activate expression of the critical lineage-determining transcription factor, Pit1, and to repress the gene encoding the lineage-inhibiting transcription factor, Hesx1, acting via TLE/Reptin/HDAC1 corepressor complexes.