Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Mesenchymal stem cells and three-dimensional-osteoconductive scaffold regenerate calvarial bone in critical size defects in swine.

Craniofacial bones protect vital organs, perform important physiological functions, and shape facial identity. Critical-size defects (CSDs) in calvarial bones, which will not heal spontaneously, are caused by trauma, congenital defects, or tumor resections. They pose a great challenge for patients and physicians, and significantly compromise quality of life. Currently, calvarial CSDs are treated either by allogenic or autologous grafts, metal or other synthetic plates that are associated with considerable complications. While previous studies have explored tissue regeneration for calvarial defects, most have been done in small animal models with limited translational value. Here we define a swine calvarial CSD model and show a novel approach to regenerate high-quality bone in these defects by combining mesenchymal stem cells (MSCs) with a three-dimensional (3D)-printed osteoconductive HA/TCP scaffold. Specifically, we have compared the performance of dental pulp neural crest MSCs (DPNCCs) to bone marrow aspirate (BMA) combined with a 3D-printed HA/TCP scaffold to regenerate bone in a calvarial CSD (>7.0 cm2 ). Both DPNCCs and BMA loaded onto the 3D-printed osteoconductive scaffold support the regeneration of calvarial bone with density, compression strength, and trabecular structures similar to native bone. Our study demonstrates a novel application of an original scaffold design combined with DPNCCs or BMA to support regeneration of high-quality bone in a newly defined and clinically relevant swine calvarial CSD model. This discovery may have important impact on bone regeneration beyond the craniofacial region and will ultimately benefit patients who suffer from debilitating CSDs.

A Pre-clinical Animal Model of Secondary Head and Neck Lymphedema.

Head and neck lymphedema (HNL) is a disfiguring disease affecting over 90% of patients treated for head and neck cancer. Animal models of lymphedema are used to test pharmacologic and microsurgical therapies; however, no animal model for HNL is described in the literature to date. In this study we describe the first reproducible rat model for HNL. Animals were subjected to two surgical protocols: (1) lymphadenectomy plus irradiation; and (2) sham surgery and no irradiation. Head and neck expansion was measured on post-operative days 15, 30 and 60. Magnetic resonance imaging (MRI) was acquired at the same time points. Lymphatic drainage was measured at day 60 via indocyanine green (ICG) lymphography, after which animals were sacrificed for histological analysis. Postsurgical lymphedema was observed 100% of the time. Compared to sham-operated animals, lymphadenectomy animals experienced significantly more head and neck swelling at all timepoints (P < 0.01). Lymphadenectomy animals had significantly slower lymphatic drainage for 6 days post-ICG injection (P < 0.05). Histological analysis of lymphadenectomy animals revealed 83% greater subcutis thickness (P = 0.008), 22% greater collagen deposition (P = 0.001), 110% greater TGFß1+ cell density (P = 0.04), 1.7-fold increase in TGFß1 mRNA expression (P = 0.03), and 114% greater T-cell infiltration (P = 0.005) compared to sham-operated animals. In conclusion, animals subjected to complete lymph node dissection and irradiation developed changes consistent with human clinical postsurgical HNL. This was evidenced by significant increase in all head and neck measurements, slower lymphatic drainage, subcutaneous tissue expansion, increased fibrosis, and increased inflammation compared to sham-operated animals.