Origin Of Stromal Cells Research Articles

A seed or soil problem in early endometriosis: stromal cell origin drives cellular invasion and coupling over mesothelial cell origin

To study the role of the mesothelial cells in early endometriosis lesion formation by assessing in vitro cell to cell communication and invasion of endometrial cells across a mesothelial cell monolayer, with both cell types derived from both endometriosis and control patients. Laboratory based experimental study SETTING: University hospital and laboratory PATIENT(S): Consenting reproductive aged women who underwent laparoscopy for gynecologic reasons and were confirmed to either have endometriosis with pathology tissue diagnosis (n=8) or no endometriosis (n=8) at the time of surgery INTERVENTION: Primary stromal cells cultured from endometrial pipelle biopsies and primary mesothelial cells cultured from peritoneal explants were utilized in trans-mesothelial invasion assays and gap junction coupling assays. Comparison of potential for lesion formation, using in vitro models, of both primary endometrial and mesothelial cells from endometriosis and control patients, establishing the former as the primary disease driver. When comparing mesothelial cells from control patients to mesothelial cells from endometriosis patients, there was no significant difference in the amount of stromal cell invasion across either barrier. In contrast, when comparing stromal cell origin, the amount of invasion by endometriosis stromal cells was greater than control stromal cells regardless of whether the mesothelial cell monolayer was derived from disease or control patients. Additionally, primary mesothelial cells induced more gap junction coupling, a requirement for invasion, in stromal cells from endometriosis than control patients, again independent of mesothelial origin. The notable exception was mesothelial cells derived from endometriotic lesion affected areas that showed depressed ability to support invasion. While both endometrial and mesothelial cells need to function for establishment of endometriosis lesions, the endometrium seems to be the key player, serving as an ideal target for diagnostic strategies and therapeutic intervention. This notion is consistent with prior studies, however we are the first to directly test both primary mesothelial and endometrial cells from endometriosis and control patients to compare propensities for mesothelial invasion.

Heterogeneous effects of S100 proteins during cell interactions between immune cells and stromal cells from synovium or skin.

Cell interactions represent an important mechanism involved in the pathogenesis of chronic inflammation. The key S100 proteins A8 and A9 have been studied in several models of chronic inflammatory diseases with highly heterogeneous conclusions. In this context, the aim of this study was to determine the role of cell interactions on S100 protein production and their effect on cytokine production during cell interactions, between immune and stromal cells from synovium or skin. Peripheral blood mononuclear cells (PBMC) were cultured alone or with synoviocytes or skin fibroblasts, with or without phytohemagglutinin, exogenous A8, A9, A8/A9 proteins or anti-A8/A9 antibody. Production of IL-6, IL-1β, IL-17, TNF, A8, A9, and A8/A9 was measured by ELISA. Cell interactions with synoviocytes had no effect on A8, A9, or A8/A9 secretion, while cell interactions with skin fibroblasts decreased A8 production. This highlights the importance of stromal cell origin. The addition of S100 proteins in co-cultures with synoviocytes did not increase the production of IL-6, IL-17, or IL-1β, except for an increase of IL-6 secretion with A8. The presence of anti-S100A8/A9 antibody did not show obvious effects. Low concentration or absence of serum in the culture medium decreased the production of IL-17, IL-6, and IL-1β but despite these conditions, the addition of S100 proteins did not increase cytokine secretion. In conclusion, the role of A8/A9 in cell interactions during chronic inflammation appears complex and heterogeneous, depending on multiple factors, notably the origin of stromal cells that can affect their secretion.

Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration.

Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic-acid- and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.

Adrenal hemangioblastoma.

Hemangioblastoma (HB) is a rare benign tumor that most commonly occurs in the cerebellum. HB is composed of neoplastic stromal cells and abundant small vessels. However, the exact origin of stromal cells is controversial. Extraneural HBs have been reported in a small series, and peripheral HBs arising in the adrenal gland are extremely rare. Herein, we report a case of sporadic adrenal HB in a 54-year-old woman. The tumor was a well-circumscribed, yellow mass measuring 4.2 cm in diameter. Histologically, the tumor was composed of small blood vessels and vacuolated stromal cells with clear cytoplasm. On immunohistochemical stain, the stromal cells were positive for S-100 protein, neuron-specific enolase, and synaptophysin. The tumor did not reveal mutation of VHL alleles. We herein present a case of HB of the adrenal gland and review of the literature.

Central giant cell granulomas of the jaws stromal cells harbour mutations and have osteogenic differentiation capacity, in vivo and in vitro.

Central giant cell granulomas (CGCG) of the jaws are osteolytic lesions that may behave aggressively and respond poorly to surgery. Microscopically, in addition to giant cells, there is a mononuclear cell population composed of macrophage/monocytic cells and spindle-shaped cells of mesenchymal origin. Seventy two percent of these tumours harbour mutually exclusive TRPV4, KRAS and FGFR1mutations. We aimed to assess the mutational status of mononuclear and giant cells and the osteogenic potential of stromal cells in vitro and in vivo. We screened CGCG for signature mutations and used laser-capture microdissection to demonstrate that the mutations are restricted to the mononuclear cells. Additionally, we established CGCG primary cell culture and observed that the cells retained the mutations throughout passages. By flow cytometry, we observed predominance of CD14- CD51- CD61- cells, consistent with the expected profile for stromal cells. Considering the mesenchymal origin of stromal cells, we assessed the osteogenic differentiation potential of CGCG cells in culture by cytochemistry (von Kossa and alizarin red staining), alkaline phosphatase (ALP) activity assay and gene expression of osteogenic markers. CGCG cells presented self-capacity to increase ALP levels in a time-dependent manner and under osteogenic induction presented increasing number of calcium deposits, and overall higher expression of osteocalcin, RUNX2, ALPL and osteopontin than cells without osteogenic induction. A patient-derived xenograft model for CGCG was established, and osteoid material deposition was observed. Collectively, the results confirm that the signature mutations are restricted to stromal cells in CGCG, and the in vitro and in vivo results support that these cells have the capacity to differentiate into osteoblasts, in line with the bone formation often observed in the stroma of these lesions.

Synoviocytes and skin fibroblasts show opposite effects on IL-23 production and IL-23 receptor expression during cell interactions with immune cells

BackgroundThe IL-23/IL-17 axis is involved in inflammatory diseases including arthritis and psoriasis. However, the response to IL-23 or IL-17 inhibitors is different depending on the disease. The aim was to compare the effects of interactions between immune and stromal cells on the IL-23 axis to understand these differences.MethodsPeripheral blood mononuclear cells were co-cultured with RA synoviocytes or Pso skin fibroblasts, with or without phytohemagglutinin, IL-23, or anti-IL-23 antibody. Production of IL-6, IL-1β, IL-23, IL-17, IL-12, and IFNγ was measured by ELISA. IL-23 and cytokine receptor gene expression (IL-17RA, IL-17RC, IL-12Rβ1, IL-12Rβ2, and IL-23R) was analyzed by RT-qPCR. IL-12Rβ1 and IL-23R subunits were analyzed by flow cytometry.ResultsThe production of IL-6, IL-1β, IL-17, IL-12, and IFNγ with synoviocytes or skin fibroblasts was rather similar, and cell interactions with immune cells increased their production, specifically that of IL-17. A major difference was observed for IL-23. Interactions with synoviocytes but not with skin fibroblasts decreased IL-23 secretion while mRNA level was increased, mainly with synoviocytes, reflecting a major consumption difference. IL-23 addition had only one effect, the increase of IL-17 secretion. Cell activation induced similar effects on cytokine receptor gene expression in co-cultures with synoviocytes or skin fibroblasts. The key difference was the cell interaction effects depending on the stromal cell origin. Interactions with synoviocytes increased the expression of both IL-23 receptor subunits at mRNA levels and IL-23R at the surface expression level while interactions with skin fibroblasts decreased their expression at the mRNA level and had no effect at the surface expression level.ConclusionInteractions between immune and stromal cells are crucial in cytokine production and their receptor expression. The origin of stromal cells had a major influence on the production of IL-23 and its receptor expression. Such differences may explain part of the heterogeneity in treatment response.

Giant Fibrothecoma of the Ovary in a Young Patient a Case Report

Fibrothecomas are benign ovarian stromal tumors, they are rare tumors of gonadal stromal cell origin that represent 3-4% of all ovarian tumors. It commonly occurs in post-menopausal women. The clinical presentation is often nonspecific, whereas patients more frequently present with a pelvic mass, metrorrhagia, and pelvic pain. We present a 35-year-old patient, nulli-pregnant, with no personal or family pathological history, who attended a medical consultation for presenting progressive abdominal distention of 6 months of evolution in addition to abdominal pain in the last 2 months type colic which increased during her menstrual periods concomitantly alteration in your defecatory habits. Abdominal ultrasound was performed, finding a solid intrapelvic mass of approximately 14x10x10 cm in diameter of probable left ovarian origin, free fluid in the Douglas space, compression and displacement of intestinal loops and bladder. The patient underwent surgery and an exploratory laparotomy was performed, finding a pelvic tumor adhered to the tube and left ovary, in addition to ascites fluid in the abdominal cavity, complete resection of the tumor, ovary and left salpingue was performed.

Role of imprint cytology in the diagnosis of ovarian neoplasms

Primary ovarian neoplasms constitute a heterogenous group of benign and malignant tumors of epithelial, sex cord–stromal, mesenchymal and germ cell origin. Secondary tumors constitute a minority. The management of benign and malignant ovarian neoplasms varies and it is here that imprint cytology plays a crucial role in diagnosis. It provides a rapid intraoperative diagnosis which will decide further treatment course for the patient. Imprint cytology of ovarian neoplasms is simple, inexpensive, challenging and provides a rapid diagnosis with excellent cellular details. The aim of the present study is to determine the role of imprint cytology in the diagnosis of ovarian neoplasms. A retrospective study was conducted in the department of pathology. A total of 53 cases were included in the study. In 48 cases, the imprint cytology findings correlated with the histopathological diagnosis. 5 cases did not correlate. Epithelial ovarian tumors accounted for the majority, (85%) followed by germ cell tumors (9.4%) and sex cord stromal tumors (5.6%). The sensitivity and specificity were 93.75% and 100% respectively. Thus imprint cytology is an effective cytological method in the diagnosis of ovarian neoplasms. Knowledge of specific cytological features for each tumor type helps in accurate diagnosis which in turn is valuable in immediate appropriate treatment and management of patients with benign or malignant neoplasms.

Coexistence of Stump Appendicitis and Ovarian Fibro-Thecoma in a Young Women with Recurrent Right Iliac Fossa Pain During Pregnancy; A Rare Case Report

Ovarian Fibro-thecoma is a rare, benign, sex cord-stromal neoplasm, with a typically unilateral location in the ovary, characterized by mixed features of both fibroma and thecoma. Ovarian Fibro-thecoma is Uncommon tumor of gonadal stromal cell origin accounting for 3-4% of all ovarian tumors. We describe a rare case of Fibro-thecoma in a 27- year women with a history of recurrent right iliac fossa pain during pregnancy associated with fever and vomiting with previous history of laparotomy for appendicular abscess 10 years back. She presented to us during pregnancy with this complain for which she was managed conservatively. She did not maintain her follow up regularly at our hospital and visited again after delivery of her baby with a still birth outcome with a newly diagnosed complex bilateral ovarian cyst demonstrated on ultrasound and computed tomography showed inflammatory Right sided tubo-ovarian mass along with inflammatory thickening of ileum in right lower quadrant adjacent to right ovarian mass lesion. The patient underwent laparotomy for this with the removal of mass along with the removal of appendicular stump for appendicular stump appendicitis which was diagnosed intraoperatively. The finding from histopathological examination of the mass was consistent with the diagnosis of Fibro-thecoma.

Consensus International Council for Commonality in Blood Banking Automation–International Society for Cell & Gene Therapy statement on standard nomenclature abbreviations for the tissue of origin of mesenchymal stromal cells

The Cellular Therapy Coding and Labeling Advisory Group of the International Council for Commonality in Blood Banking Automation and the International Society for Cell & Gene Therapy mesenchymal stromal cell (MSC) committee are providing specific recommendations on abbreviating tissue sources of culture-adapted MSCs. These recommendations include using abbreviations based on the ISBT 128 terminology model that specifies standard class names to distinguish cell types and tissue sources for culture-adapted MSCs. Thus, MSCs from bone marrow are MSC(M), MSCs from cord blood are MSC(CB), MSCs from adipose tissue are MSC(AT) and MSCs from Wharton's jelly are MSC(WJ). Additional recommendations include using these abbreviations through the full spectrum of pre-clinical, translational and clinical research for the development of culture-adapted MSC products. This does not apply to basic research focused on investigating the developmental origins, identity or functionalities of endogenous progenitor cells in different tissues. These recommendations will serve to harmonize nomenclature in describing research and development surrounding culture-adapted MSCs, many of which are destined for clinical and/or commercial translation. These recommendations will also serve to align research and development efforts on culture-adapted MSCs with other cell therapy products.

Audit of Clinicopathological Analysis of Ovarian Tumour in a Tertiary Hospital

Background: Ovarian tumors are a heterogenous group of neoplasia of epithelial, stromal and germ cell origin. Each class there are different behaviors ranging from benign to highly aggressive malignant tumor. The management depends on the histological type, presentation and stage of the disease. Aim: To ascertain the incidence, the age of distribution, the parity, the clinical presentation, and the histological types. Materials and methods: It was a retrospective study and information was retrieved from patient’s files in the department of Obstetrics and Gynecology as well as the histology forms from the histopathology department of the teaching hospital Result: A total of 82 cases were studied out of 3,084 gynecological admissions within the study period giving an incidence of 2.7%. The germ cell tumor was noted to be the commonest gynecological tumor. Conclusion: Clinical data and sonographic findings can help narrow our differential diagnosis. However, histology is indispensable in making the final diagnosis and thus helping to determine the appropriate treatment management of patient.

A Case Report of Ovarian Fibrothecoma in a Premenopausal Women with Recurrent Menorrhagia

BACKGROUND: Ovarian fibrothecoma is a rare, benign, sex cord-stromal neoplasm, with a typically unilateral location in the ovary, characterized by mixed features of both fibroma and thecoma. Ovarian fibrothecoma is uncommon tumor of gonadal stromal cell origin accounting for 3-4% of all ovarian tumours.
 CASE PRESENTATION: We presented a rare case of a 46-year-old patient with recurrent menorrhagia in the past two years with no previous medical, surgical or gynecological history. She underwent two times curettage procedures. At the admission to hospital ultrasonography showed a homogenous solid right ovarian mass of size 2.5 cm x 3.5 cm. Endometrial curettage revealed simple hyperplasia of the endometrium. Diagnostic evaluation and surgical management are discussed along with a brief review of the literature. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was carried out. Histopathology confirmed fibrothecoma of the ovary, proliferative endometrium with hyperplasia without atypia and multiple uterine fibroids.
 CONCLUSION: In all patients presenting with recurrent menorrhagia and adnexal tumor the possibility of a granulosa cell tumor must be kept in mind during evaluation.

Embryonic FAP+ lymphoid tissue organizer cells generate the reticular network of adult lymph nodes.

The induction of adaptive immunity is dependent on the structural organization of LNs, which is in turn governed by the stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace the developmental origin of mesenchymal LN stromal cells (mLNSCs) to a previously undescribed embryonic fibroblast activation protein-α (FAP)+ progenitor. FAP+ cells of the LN anlagen express lymphotoxin β receptor (LTβR) and vascular cell adhesion molecule (VCAM), but not intercellular adhesion molecule (ICAM), suggesting they are early mesenchymal lymphoid tissue organizer (mLTo) cells. Clonal labeling shows that FAP+ progenitors locally differentiate into mLNSCs. This process is also coopted in nonlymphoid tissues in response to infection to facilitate the development of tertiary lymphoid structures, thereby mimicking the process of LN ontogeny in response to infection.

Fabrication of size-controllable human mesenchymal stromal cell spheroids from micro-scaled cell sheets

Recently, stromal cell spheroids have been actively studied for use in tissue regeneration. In this study, we report a method for the fabrication of size-controllable stromal cell spheroids in different sizes from micro-scaled cell sheets (μCS) using thermosensitive hydrogels and investigated their effects on stromal cell function. Mesenchymal stromal cells isolated from different tissues such as human turbinate tissue, bone marrow, and adipose tissue were adhered selectively to each micro-pattern (squares with widths of 100 and 400 μm) on the surface of the hydrogel and formed μCS. The diameters of the spheroids were modulated by the size of the patterns (45 ± 5 and 129 ± 4 μm in diameter for the 100 and 400 μm micro-patterns, respectively) and the seeding density (129 ± 4, 149 ± 6, and 163 ± 6 μm for 5.0, 10.0, and 15.0 × 104 cells cm−2, respectively, on 400 μm micro-pattern). In addition, the spheroids were successfully fabricated regardless of stromal cell origin, and the diameter of the spheroids was also affected by cell spreading area on a cell culture dish. Stemness markers were highly expressed in the spheroids regardless of the spheroid size. Furthermore, an increase in E-cadherin and decrease in N-cadherin gene expression showed the stable formation of spheroids of different sizes. Gene expression levels of hypoxia inducible factors and secretion of vascular endothelial growth factor were increased (13.2 ± 1.4, 325 ± 83.4 and 534.3 ± 121.5 pg ng−1 DNA in a monolayer, and 100 and 400 μm micro-patterned spheroids, respectively) proportional to the diameters of the spheroids. The size of spheroids were maintained even after injection, cryopreservation and 7 d of suspension culture with high viability (∼90%). In conclusion, this novel technique to fabricate spheroids with controlled size could be widely applied in various applications that require a controlled size in regenerative medicine.

Heparin Differentially Impacts Gene Expression of Stromal Cells from Various Tissues

Pooled human platelet lysate (pHPL) is increasingly used as replacement of animal serum for manufacturing of stromal cell therapeutics. Porcine heparin is commonly applied to avoid clotting of pHPL-supplemented medium but the influence of heparin on cell behavior is still unclear. Aim of this study was to investigate cellular uptake of heparin by fluoresceinamine-labeling and its impact on expression of genes, proteins and function of human stromal cells derived from bone marrow (BM), umbilical cord (UC) and white adipose tissue (WAT). Cells were isolated and propagated using various pHPL-supplemented media with or without heparin. Flow cytometry and immunocytochemistry showed differential cellular internalization and lysosomal accumulation of heparin. Transcriptome profiling revealed regulation of distinct gene sets by heparin including signaling cascades involved in proliferation, cell adhesion, apoptosis, inflammation and angiogenesis, depending on stromal cell origin. The influence of heparin on the WNT, PDGF, NOTCH and TGFbeta signaling pathways was further analyzed by a bead-based western blot revealing most alterations in BM-derived stromal cells. Despite these observations heparin had no substantial effect on long-term proliferation and in vitro tri-lineage differentiation of stromal cells, indicating compatibility for clinically applied cell products.

Tumor‐stroma interactions differentially alter drug sensitivity based on the origin of stromal cells

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor–stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor–stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.

Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which pro-inflammatory immune cells and cytokines induce intestinal tissue damage and disability. Mesenchymal stromal cells (MSCs) exert powerful immunomodulatory effects and stimulate tissue repair. To review the current data on mesenchymal stromal cell therapy in IBD. We searched PubMed and 'ClinicalTrials.gov' databases using the terms 'mesenchymal stromal cells', 'mesenchymal stem cell transplantation', 'inflammatory bowel diseases', 'Crohn disease' and 'colitis, ulcerative'. Additional publications were identified from individual article reference lists. MSCs include inhibition of Th1/Th17 lymphocytes and recruitment of regulatory T lymphocytes, induction of antigen-presenting cells into a regulatory-like profile, and stimulation of epithelial cell differentiation and proliferation. More than 200 patients with refractory fistulas have been treated with local injections of MSCs, resulting in complete response in more than half, and in overall response in approximately two thirds of patients. In refractory luminal Crohn's disease, 49 cases of systemic MSC infusions have been reported, while trials with autologous MSCs resulted in mitigated responses, studies using allogeneic MSCs were promising, with around 60% of patients experiencing a response and around 40% achieving clinical remission. Mesenchymal stromal cells might represent a promising therapy for IBD, especially for Crohn's disease. There remain many unsolved questions concerning the optimal origin and source of mesenchymal stromal cells, dosage and modalities of administration. Moreover, mesenchymal stromal cells still need to prove their effectiveness compared with conventional treatments in randomised controlled trials.

Potential crosstalk of the interleukin-6-heme oxygenase-1-dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells.

Interleukin (IL)-6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL-6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. HO-1 expression levels in bone marrow CD138(+) cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL-6 and intracellular IL-6 mRNA expression levels. Culture of U266, RPMI8226 and CD138(+) cells with exogenous IL-6 in vitro induced high HO-1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL-6-mediated activation of the Janus kinase 2-signal transducer and activator of transcription 3 pathway. In contrast, without IL-6 coculture, enhanced HO-1 expression in U266, RPMI8226 and bone marrow CD138(+) cells from MM patients significantly inreased IL-6 mRNA expression levels and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced p38 mitogen-activated protein kinase phosphorylation. Reduced HO-1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL-6 in the bone marrow microenvironment of MM patients stimulated high HO-1 expression in MM cells and their resistance to lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, and exacerbated drug resistance and disease. This study supports the use of HO-1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.

Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling.

Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear.

Investigation of the origin of stromal and endothelial cells at the desmoplastic interface in xenograft tumor in mice

Carcinoma-associated fibroblasts found at the interface between a tumor and the normal stroma play several roles in the development of cancer, including cancer initiation, growth, and progression, thereby also affecting patient prognosis. Although recent studies have focused on carcinoma-associated fibroblasts as potential treatment targets, the origin of these fibroblasts remains unclear. One theory suggests that these cells arise from tumor cells undergoing the epithelial–mesenchymal transition, i.e., tumor cells transform into carcinoma-associated fibroblasts. Therefore, in this study, we aimed to elucidate the cellular origin of carcinoma-associated fibroblasts in a mouse xenograft model. Mice were transplanted with human lung cancer cells (H226 and A549 cells). After sacrifice, tumor masses and surrounding tissues were excised. Interestingly, the excised xenograft tissues contained a significant proportion of desmoplastic fibroblasts that exhibited strong expression of α-smooth muscle actin (SMA). Immunohistochemical staining with pan-cytokeratin, vimentin, β-catenin, E-cadherin, and CD34 showed no evidence of the epithelial–mesenchymal transition. Additional evaluation using dual-color silver in situ hybridization with dinitrophenyl-labeled human epidermal growth factor receptor 2 (HER2) and digoxigenin-labeled chromosome 17 centromere probes also showed similar results. In conclusion, our results revealed that the epithelial–mesenchymal transition may not occur in tumor xenograft models, regardless of evidence supporting this phenomenon in humans.