Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

This study was aimed to investigate the abnormal expression of PDGFRA gene in eosinophilia by FISH. Translocations of PDGFRA gene in 13 patients with eosinophilia were detected by using 4q12 three-color probe and FISH technology. Fifteen people were used as control to establish the normal cut-off value of fluorescence signal of PDGFRA. The results indicated that 1 out of 13 patients with eosinophilia was corrected and was diagnosed as CML. The fusion gene of FIP1L1-PDGFRA (F/P) was found in 2 patients and the positive rate of F/P fusion gene detected by probe 4q12 was 17% in the 12 patients with eosinophilia. Other translocation forms involving PDGFRA gene were not found. It is concluded that a variety of translocation forms of PDGFRA gene can be detected in patients with eosinophilia by using 4q12 three-color probe and FISH technology, which can provide important information for assessing diagnosis and treatment.
Chromosomes, Human, Pair 4 ; Eosinophilia ; metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Oncogene Proteins, Fusion ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; Translocation, Genetic

OBJECTIVETo study the clinical and pathologic features of gastric schwannomas.

METHODSThe macroscopic and microscopic features of 9 cases of gastric schwannoma were analyzed. Immunohistochemical study for S-100 protein, CD117, CD34, neurofilament, desmin, nestin, glial fibrillary acidic protein, platelet derived growth factor-alpha (PDGFR-α) and vimentin was carried out. Mutation analysis of c-kit gene (exon 9, 11, 13 and 17) and PDGFR-α gene (exon 12 and 18) in 1 case was examined by PCR amplification and direct sequencing.

RESULTSThe patients included 5 males and 4 females. The age of patients ranged from 42 to 81 years (median = 56.5 years). The size of the tumors ranged from 2 to 9 cm in greatest diameter. Follow-up data in 8 cases (from 1 month to 65 months) showed no evidence of recurrence or metastasis. Gross examination showed that gastric schwannomas were homogeneous, firm, yellow-white and bore no true fibrous capsule. Histologically, all cases were composed of fascicles of spindle cells associated with nuclear palisading, Verocay body formation and peripheral cuff of reactive lymphoid aggregates. Some of them showed degenerative changes including cyst formation, calcification, hemorrhage, necrosis and hyalinization. Immunohistochemical study showed that the tumor cells were strongly positive for S-100 protein and vimentin. There was various degree of staining for nestin (8/9) and glial fibrillary acidic protein (6/9). They were negative for CD117, CD34, neurofilament, desmin and smooth muscle actin. One case showed focal positivity for PDGFR-α (1/9), with no mutations found.

CONCLUSIONSGastric schwannomas share similar histologic features with conventional soft tissue schwannomas, in addition to the presence a reactive lymphoid cuff. The clinical, macroscopic, histologic and immunohistochemical features of gastric schwannomas were different from those of gastrointestinal stromal tumors and leiomyomas.

Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; Exons ; Female ; Follow-Up Studies ; Gastrectomy ; methods ; Gastrointestinal Stromal Tumors ; metabolism ; pathology ; Glial Fibrillary Acidic Protein ; metabolism ; Humans ; Intermediate Filament Proteins ; metabolism ; Leiomyoma ; metabolism ; pathology ; Leiomyosarcoma ; metabolism ; pathology ; Male ; Middle Aged ; Mutation ; Nerve Tissue Proteins ; metabolism ; Nestin ; Neurilemmoma ; metabolism ; pathology ; surgery ; Neurofibroma ; metabolism ; pathology ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism ; S100 Proteins ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; surgery ; Vimentin ; metabolism

OBJECTIVETo study the role of platelet-derived growth factor A (PDGF-A)/PDGF receptor-α (PDGFR-α) signaling pathway in the proliferation and transdifferentiation of fibroblasts (FB) into myofibroblasts (MFB) in the skin lesions of patients with systemic sclerosis (SSc).

METHODSThe primary FBs isolated from the skin lesions of SSc patients and normal adult skin cultured in vitro were examined for α-smooth muscle actin (α-SMA) using immunocytochemistry. The FBs were incubated with different concentrations of PDGF-AA and the changes in their proliferative activity were quantified with MTT assay. RT-PCR was used to determine the effects of transforming growth factor-β(1) (TGF-β(1)) and PDGF-AA, either alone or in combination, on the expression levels of PDGFR-α and α-SMA mRNA in the FBs.

RESULTSAlthough the FBs of the two groups were morphologically similar, only FBs from the skin lesion showed positive staining for &alpha;-SMA. Below the saturated concentration of PDGF, the FBs in the two groups both proliferated in a dose-dependent manner (P<0.05), but the FBs from the SSc lesions always showed a significantly higher proliferative activity (P<0.05). PDGF-AA and TGF-β(1), alone or in combination, up-regulated the expression level of PDGFR-&alpha; and &alpha;-SMA mRNA in the FBs from SSc lesions; similar results were obtained in the control FBs, except that TGF-β(1) alone did not influence PDGFR-&alpha; mRNA expression. PDGFR-&alpha; and &alpha;-SMA mRNA always showed higher expressions in FBs in SSc lesions than in the control FBs with the same treatments (P<0.05). The expression levels of PDGFR-&alpha; and &alpha;-SMA mRNA increased in the order of untreated, PDGF-AA, TGF-β(1) and PDGF-AA plus TGF-β(1) groups and showed a strong positive correlation between them (r=0.925, P<0.05).

CONCLUSIONThe FBs from the skin lesions of SSc patients have a distinct feature of transdifferentiation into MFB. Over-expression of PDGFR-&alpha; on the surface of FBs from SSc lesions can bind more PDGF-AA ligands to increase cell proliferation and promote transdifferentiation to MFB, and TGF-β(1) further enhances this effect .

Actins ; metabolism ; Adult ; Cell Proliferation ; Cell Transdifferentiation ; Cells, Cultured ; Female ; Fibroblasts ; cytology ; Humans ; Male ; Middle Aged ; Myofibroblasts ; cytology ; Platelet-Derived Growth Factor ; metabolism ; Receptor, Platelet-Derived Growth Factor alpha ; metabolism ; Scleroderma, Systemic ; metabolism ; pathology ; Signal Transduction ; Transforming Growth Factor beta ; pharmacology

OBJECTIVETo investigate the relationship between secondary mutations of c-kit/PDGFR&alpha; resistance to imatinib mesylate and the efficacy of sunitinib in patients with gastrointestinal stromal tumor (GIST).

METHODSFive pairs specimens were collected before and after imatinib mesylate resistance. DNA for molecular genetic investigation was extracted from formalin-fixed, paraffin-embedded tissues. Mutational analysis was performed by using PCR and direct sequencing.

RESULTSFive pairs of specimens were collected before and after imatinib mesylate resistance from 5 GIST patients. C-kit exon 11 mutations were detected in 3 patients, which were all acquired mutations, including c-kit exon 13 V654A, c-kit exon 13 V654E and c-kit exon 17 N822K, after imatinib mesylate resistance. Furthermore, after sunitinib treatment, 3 patients had stable disease and progression free survival (PFS) were 3.5 months, 4.4 months and 3.8 months, respectively. C-kit exon 9 mutations were detected in 2 patients with no acquired mutations after imatinib mesylate resistance. And the both had partial response from sunitinib, following with 13.1 months and 12.0 months PFS respectively.

CONCLUSIONThe c-kit/PDGFR&alpha; genotypes after imatinib mesylate resistance may both relate to primary mutations and efficacy of sunitinib treatment.

Antineoplastic Agents ; therapeutic use ; Benzamides ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Exons ; Female ; Gastrointestinal Stromal Tumors ; drug therapy ; genetics ; Genotype ; Humans ; Imatinib Mesylate ; Indoles ; therapeutic use ; Male ; Middle Aged ; Mutation ; Piperazines ; therapeutic use ; Proto-Oncogene Proteins c-kit ; genetics ; metabolism ; Pyrimidines ; therapeutic use ; Pyrroles ; therapeutic use ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism

Metastasis represents by far the most feared complication of prostate carcinoma and is the main cause of death for patients. The skeleton is frequently targeted by disseminated cancer cells and represents the sole site of spread in more than 80% of prostate cancer cases. Compatibility between select malignant phenotypes and the microenvironment of colonized tissues is broadly recognized as the culprit for the organ-tropism of cancer cells. Here, we review our recent studies showing that the expression of platelet-derived growth factor receptor alpha (PDGFR&alpha;) supports the survival and growth of prostate cancer cells in the skeleton and that the soluble fraction of bone marrow activates PDGFR&alpha; in a ligand-independent fashion. Finally, we offer pre-clinical evidence that this receptor is a viable target for therapy.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Bone Marrow ; enzymology ; pathology ; Bone Neoplasms ; prevention & control ; secondary ; Enzyme Activation ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptor, Platelet-Derived Growth Factor alpha ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Signal Transduction ; Transcriptional Activation

Recent collaborative, large-scale genomic profiling of the most common and aggressive brain tumor glioblastoma multiforme(GBM) has significantly advanced our understanding of this disease. The gene encoding platelet-derived growth factor receptor alpha(PDGFR&alpha;) was identified as the third of the top 11 amplified genes in clinical GBM specimens. The important roles of PDGFR&alpha; signaling during normal brain development also implicate the possible pathologic consequences of PDGFR&alpha; over-activation in glioma. Although the initial clinical trials using PDGFR kinase inhibitors have been predominantly disappointing, diagnostic and treatment modalities involving genomic profiling and personalized medicine are expected to improve the therapy targeting PDGFR&alpha; signaling. In this review, we discuss the roles of PDGFR&alpha;signaling during development of the normal central nervous system(CNS) and in pathologic conditions such as malignant glioma. We further compare various animal models of PDGF-induced gliomagenesis and their potential as a novel platform of pre-clinical drug testing. We then summarize our recent publication and how these findings will likely impact treatments for gliomas driven by PDGFR&alpha; overexpression. A better understanding of PDGFR&alpha; signaling in glioma and their microenvironment, through the use of human or mouse models, is necessary to design a more effective therapeutic strategy against gliomas harboring the aberrant PDGFR&alpha; signaling.
Animals ; Antineoplastic Agents ; therapeutic use ; Autocrine Communication ; Brain Neoplasms ; drug therapy ; genetics ; metabolism ; Central Nervous System ; cytology ; embryology ; metabolism ; Disease Models, Animal ; Glioblastoma ; drug therapy ; genetics ; metabolism ; Glioma ; drug therapy ; genetics ; metabolism ; Humans ; Neurons ; cytology ; metabolism ; Protein Kinase Inhibitors ; therapeutic use ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism

Over the past 60 years, investigators of basic science, pathology, and clinical medicine have studied gastrointestinal stromal tumor (GIST) and made minor advances in patient care. Recent discoveries have led to an understanding of the biological role of KIT and platelet-derived growth factor receptor-&alpha; in GIST and the development of the tyrosine kinase inhibitor imatinib mesylate (Gleevec, formerly STI-571), one of the most exciting examples of targeted therapy to date. The success of targeted therapy in GIST has lead to new developments in our understanding of the medical and surgical management of the disease. Intense study of GIST may lead to new paradigms in the management of cancer.
Antineoplastic Agents ; therapeutic use ; Benzamides ; Combined Modality Therapy ; Drug Delivery Systems ; Gastrointestinal Neoplasms ; drug therapy ; genetics ; pathology ; surgery ; Gastrointestinal Stromal Tumors ; drug therapy ; genetics ; pathology ; surgery ; Humans ; Imatinib Mesylate ; Mutation ; Piperazines ; therapeutic use ; Protein Kinase Inhibitors ; therapeutic use ; Proto-Oncogene Proteins c-kit ; genetics ; metabolism ; Pyrimidines ; therapeutic use ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism

Antigens, CD34 ; metabolism ; Carcinoma, Signet Ring Cell ; genetics ; metabolism ; pathology ; surgery ; Codon ; Diagnosis, Differential ; Exons ; Female ; Follow-Up Studies ; Gastrectomy ; methods ; Gastrointestinal Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Gastrointestinal Stromal Tumors ; genetics ; metabolism ; pathology ; surgery ; Humans ; Melanoma ; metabolism ; pathology ; Middle Aged ; Neurilemmoma ; metabolism ; pathology ; Point Mutation ; Proto-Oncogene Proteins c-kit ; metabolism ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism

OBJECTIVETo study the immunophenotype and c-kit or platelet derived growth factor receptor alpha (PDGFRA) gene mutations in CD117-negative gastrointestinal stromal tumors (GISTs).

METHODSTen cases of GISTs with typical histologic features but no CD117 expression were retrieved from the archival of Department of Pathology, Peking Union Medical College Hospital, China. The cases were further evaluated for the presence of c-kit exons 9, 11, 13 and 17 mutations and PDGFRA exons 12 and 18 mutations. DNA was extracted from the paraffin-embedded tumor tissue. The PCR products were sequenced directly for the mutations. An immunohistochemical study for CD117, CD34, smooth muscle actin, desmin, S-100 protein, WT-1 and DOG-1 was also performed.

RESULTSEight of the 10 cases had the mutation tests completed. C-kit mutation in exon 9 was detected in only one case. Amongst the 10 cases studied, CD34 was expressed in 9 cases. Smooth muscle actin was focally positive in 2 cases. None of them expressed desmin or S-100 protein. DOG-1 and WT-1 were diffusely positive in 5 and 4 cases, respectively. In addition, DOG1 was diffusely but weakly positive in 1 case and focally expressed in 2 cases. Three cases were focally positive for WT-1.

CONCLUSIONPathologic diagnosis of CD117-negative GISTs can be facilitated with the application of a panel of immunohistochemical markers, including DOG-1 and WT-1.

Actins ; metabolism ; Adult ; Aged ; Anoctamin-1 ; Antigens, CD34 ; metabolism ; Chloride Channels ; Exons ; Female ; Gastrointestinal Stromal Tumors ; genetics ; metabolism ; pathology ; Humans ; Immunophenotyping ; Male ; Membrane Proteins ; metabolism ; Middle Aged ; Mutation ; Neoplasm Proteins ; metabolism ; Proto-Oncogene Proteins c-kit ; genetics ; metabolism ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; metabolism ; WT1 Proteins ; metabolism ; Young Adult