Bone Marrow-derived Myofibroblasts Research Articles

Human hepatocytes response to pathological shifts in liver fibrosis

Protracted liver assault results in hepatic fibrosis, frequently advancing into cirrhosis, hepatic failure, portal hypertension and hepatocellular carcinoma or degeneration. Hepatic fibrosis emanates from the wound-healing response of the liver to persistent assault. Following acute liver insult, such as viral hepatitis, parenchymal cells regenerate and substitute the necrotic or apoptotic cells. A salient proportion of the affected population of NAFLD advances to nonalcoholic steatohepatitis, NASH, and is characterised by inflammation, hepatocellular swelling, with ensuing eruption of deteriorating fibrosis. An untreated or persistent NASH can progressively culminate in liver cirrhosis and hepatocellular carcinoma. Chronic liver derangement results in pathologic ECM protein or liver fibrosis aggregation. In essence, the encompassing characterisation of human ECM molecular composition provides for excursions into mechanisms of liver disease or hepatocellular degeneration. Hepatocytes are characterized by elevated mitochondrial concentrations. The difference between NASH and fibrosis is evident that the progression of NASH to cirrhosis commences as inflamed liver tissue evolves into scar tissue or fibrosis that is capable of obliterating the liver from optimum functionality. A third or more of persons presenting with NASH develop cirrhosis , and also elevates and accelerates the risk in the development of liver cancer. The hepatic stellate cells are responsible for liver fibrosis as they are substantially involved in the initiation, progression, and regression of liver fibrosis via the secretion of fibrogenic factors which promote portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts in the formation of collagen, and consequential propagation of fibrosis.

Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction.

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts L-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury

The chronic phase following toxin-induced acute kidney injury (AKI) is characterized by robust inflammation and progressive kidney fibrosis. Interferon regulatory factor 4 (IRF-4) is a type of multifunctional transcription factor that has been deeply linked to inflammation and fibrotic diseases. However, the role of IRF-4 in kidney damage and renal fibrosis after toxin-induced AKI remain to be explored. In this work, we examined the effect of IRF-4 deficiency on inflammation and kidney fibrosis in an AKI-chronic kidney disease (CKD) transition model induced by folic acid (FA) injury. We showed that FA treatment resulted in severe acute tubular injury followed by inflammatory reaction and interstitial fibrosis in wild-type mice. A sharp elevation of IRF-4 levels was observed in FA-injured kidneys. IRF-4 knockout led to a substantial reduction of extracellular matrix (ECM) proteins deposition and inhibited myofibroblasts transformation in the kidneys of mice subjected to FA treatment. In addition, IRF-4 ablation impaired F4/80+ macrophages and CD3+ T lymphocytes infiltration into the FA-injured kidneys. Loss of IRF-4 reduced the production of inflammatory molecules such as CXCL16, IL-18, IL-6, and TGF-β1 in the kidneys in response to FA stress. Following FA injury, the kidneys of IRF-4 knockout mice had fewer bone marrow-derived myofibroblasts than wild-type controls. Moreover, IRF-4 disruption inhibited macrophages to myofibroblasts differentiation in the kidneys in response to FA stimuli. In vitro, IL-4 stimulated expression of α-smooth muscle actin and ECM proteins and promoted M2 macrophages to myofibroblasts transition in mouse bone marrow-derived monocytes, which was abolished in the absence of IRF-4. Thus, we identified an important role of IRF-4 in the pathogenesis of progressive CKD following FA-induced AKI.

Natural killer T cell/IL-4 signaling promotes bone marrow-derived fibroblast activation and M2 macrophage-to-myofibroblast transition in renal fibrosis

Renal fibrosis is a histological manifestation of chronic kidney disease. Natural killer T (NKT) cells have a critical role in the pathogenesis of fibrotic disorder. However, the role of NKT cells in regulating kidney fibrosis remains largely unknown. In the current study, we showed that the percentages of NKT+ cells and NKT+-IL-4+ cells were notably increased in folic acid (FA) and obstructive nephropathy. CD1d deficiency protected mice from renal fibrosis induced by FA and obstructive injury. Specifically, Loss of CD1d reduced bone marrow-derived myofibroblasts and CD206+/α-smooth muscle actin+ cells in the kidneys of injured mice. But mice treated with α-galactosylceramide (α-GC, a specific activator of NKT cells) developed more severe fibrosis, accumulated more myeloid myofibroblasts and M2 macrophages-myofibroblasts transition (M2MMT) cells in FA injured kidneys. Furthermore, IL-4 expression was markedly reduced in CD1d deficiency mice but increased in α-GC-treated mice. Administration of IL-4 abrogates the inhibiting effect of CD1d deficiency on renal fibrosis, bone marrow–derived fibroblasts activation, and M2MMT in FA injured kidneys. Conversely, pharmacological inhibition of IL-4 attenuated the development of renal fibrosis, decreased bone marrow-derived myofibroblasts, and suppressed M2MMT. Thus, this study revealed a novel role of NKT cells in the bone marrow-derived fibroblasts activation and M2MMT during renal fibrosis. Targeting NKT cell/IL-4 signaling may be an effective treatment for renal fibrosis.

Pharmacological inhibition of SETD7 by PFI-2 attenuates renal fibrosis following folic acid and obstruction injury

Renal fibrosis is the common pathological hallmark of chronic kidney disease, and SET domain containing lysine methyltransferase 7 (SETD7) promote considerably renal fibrosis. However, the signaling mechanisms underlying SETD7 driving renal fibrosis are not fully understood. Here, we investigated the role of SETD7 in M2 macrophages-myofibroblasts transition and the myeloid fibroblasts activation in folic acid and obstruction-induced renal fibrosis. Mice treated with PFI-2, an inhibitor of SETD7, presented less bone marrow-derived myofibroblasts, fewer CD206+/α-smooth muscle actin + cells and developed less renal fibrosis (P＜0.01). Furthermore, SETD7 inhibition reduced the infiltration of inflammatory cells and decreased the production of pro-inflammatory cytokines and chemokines in the kidneys after folic acid treatment (P＜0.01). Finally, SETD7 inhibition suppressed the accumulation of NF-κB p65+ cells in folic acid nephropathy (P＜0.01). Taken together, SETD7 mediates M2 macrophages-myofibroblasts transition, bone marrow-derived myofibroblasts activation, and inflammation response in the development of renal fibrosis.

Functional expression cloning of molecules inducing CD34 expression in bone marrow-derived stromal myofibroblasts

We have previously shown a fraction of stromal fibroblasts/myofibroblasts (Fibs) from leukemic bone marrow cells expresses leukemia-specific transcripts along with hematopoietic and Fib-related markers. Normal bone marrow-derived Fibs (nFibs) do not express CD34 or CD45; however, nFibs may express hematopoietic markers with some specific stimulations. CD34 expression was detected in nFib cultures following the addition of a culture supernatant of blood mononuclear cells stimulated with phytohemagglutinin (PHA)-P. To identify the molecules responsible for inducing CD34 expression in nFibs, cDNA clones were isolated using functional expression cloning with a library constructed from PHA-P-stimulated human blood mononuclear cells. Positive clones inducing CD34 transcription in nFibs were selected. We confirmed that an isolated positive cDNA clone encoded human interleukin (IL)-1 beta (β). CD34 expression was observed in the nFib cultures with recombinant human (rh) IL-1β protein. And CD34 transcription was suppressed when a rhIL-1β neutralizing antibody was added to the IL-1β-stimulated nFib cultures. nFibs expressed gp130 and IL-6 receptors, and CD45 expression was detected in nFibs cultured with rhIL-1β and rhIL-6. Chronic myelogenous leukemia (CML) cells reportedly respond well to IL-1β. When CML-derived Fibs were cultured with rhIL-1β and rhIL-6, CD45-positive cells increased in number. Cell fate may be influenced by an external specific stimulation without gene introduction.

Bone Marrow-Derived Myofibroblasts Promote Gastric Cancer Metastasis by Activating TGF-β1 and IL-6/STAT3 Signalling Loop.

BackgroundMurine bone marrow-derived myofibroblasts (BMFs) have previously been shown to promote gastric cancer growth. However, whether BMFs promote gastric cancer cell metastasis remains largely unknown.MethodsWound healing assay, Transwell invasion and migration assay and 3D organotypic co-culture systems were conducted to study the effects of BMFs on invasion and migration of gastric cancer cells and the invasion and migration ability of gastric cancer stem cell-like cells (CSC-LCs) induced by BMFs. We employed two animal model to study the role of BMFs on the in vivo metastasis of gastric cancer cells and the metastatic ability of gastric BMF-induced CSC-LCs. A human gastric cancer tissue microarray and TCGA gastric cancer database were analysed to study the relationship between the expression of IL-6 and TGF-β1 and clinicopathological characteristics and survival in gastric cancer.ResultsWe found that BMFs promoted the in vitro migration and invasion of gastric cancer cells. BMFs promoted liver, lung, subcutaneous, and splenic metastases of MKN28 cells in the spleen injection liver metastasis model and co-injection of caudal vein (IOCV) mouse model. BMFs reprogrammed non-gastric cancer stem cell (CSC) to CSC-LCs and enhanced CSC-LC migration and metastasis. BMF-derived IL-6 and gastric cancer cell-secreted TGF-β1 mediated the interaction between BMFs and gastric cancer cells, promoting tumour metastasis. BMFs enhanced the expressions of STAT3 and p-STAT3 in co-cultured gastric cancer cells. A combination of Napabucasin and Galunisertib exhibited the strongest inhibition of cell migration compared to when administered alone. Gastric cancer tissue array and TCGA database indicated that the overexpression of IL-6 and TGF-β1 was associated with gastric cancer metastasis.ConclusionOur results demonstrated that BMFs promote gastric cancer metastasis through the activation of the TGF-β1 and IL-6/STAT3 signalling pathways. Targeting the inhibition of these interactions may be a potent therapeutic strategy for addressing gastric cancer metastasis.

Phosphoinositide 3-kinase γ deficiency attenuates kidney injury and fibrosis in angiotensin II-induced hypertension.

We have shown that the CXCL16/CXCR6 axis plays a critical role in recruiting inflammatory cells and bone marrow-derived fibroblasts into the kidney leading to renal injury and fibrosis. However, the underlying signaling mechanisms are not known. In the present study, we examined the role of phosphoinositide-3 kinase γ (PI3Kγ) signaling in the recruitment of inflammatory cells and bone marrow-derived fibroblasts into the kidney and development of renal injury and fibrosis in an experimental model of hypertension induced by angiotensin II. Blood pressure was comparable between wild-type (WT) and PI3Kγ knockout (KO) mice at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between WT and PI3Kγ KO mice. Compared with WT mice, PI3Kγ KO mice were protected from angiotensin II-induced renal dysfunction and injury and developed less proteinuria. PI3Kγ deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidney and inhibited total collagen deposition and extracellular matrix protein production in the kidney in response to angiotensin II. PI3Kγ deficiency inhibited the infiltration of F4/80+ macrophages and CD3+ T cells into the kidney and reduced gene expression levels of pro-inflammatory cytokines in the kidney following angiotensin II treatment. Finally, inhibition of PI3Kγ suppressed CXCL16-induced monocyte migration in vitro. These results indicate that PI3Kγ mediates the influx of macrophages, T cells and bone marrow-derived fibroblasts into the kidney resulting in kidney injury and fibrosis.

Tripeptide Arg-Gly-Asp (RGD) modifies the molecular mechanical properties of the non-muscle myosin IIA in human bone marrow-derived myofibroblasts seeded in a collagen scaffold.

Mesenchymal stem cells (MSCs) were obtained from human bone marrow and amplified in cultures supplemented with human platelet lysate in order to generate myofibroblasts. When MSCs were seeded in solid collagen scaffolds, they differentiated into myofibroblasts that were observed to strongly bind to the substrate, forming a 3D cell scaffold network that developed tension and shortening after KCl stimulation. Moreover, MSC-laden scaffolds recapitulated the Frank-Starling mechanism so that active tension increased in response to increases in the initial length of the contractile system. This constituted a bioengineering tissue that exhibited the contractile properties observed in both striated and smooth muscles. By using the A. F. Huxley formalism, we determined the myosin crossbridge (CB) kinetics of attachment (f1) and detachment (g1 and g2), maximum myosin ATPase activity, molar myosin concentration, unitary CB force and maximum CB efficiency. CB kinetics were dramatically slow, characterizing the non-muscle myosin type IIA (NMMIIA) present in myofibroblasts. When MSCs were seeded in solid collagen scaffolds functionalized with Arg-Gly-Asp (RGD), contractility increased and CB kinetics were modified, whereas the unitary NMMIIA-CB force and maximum CB efficiency did not change. In conclusion, we provided a non-muscle bioengineering tissue whose molecular mechanical characteristics of NMMIIA were very close to those of a non-muscle contractile tissue such as the human placenta.

Sa1711 – Bone Marrow-Derived Myofibroblasts Promotes Gastric Cancer Metastasis Through Activating TGF-Β1 and Il-6/Stat3 Signal Pathways

Sa1711 – Bone Marrow-Derived Myofibroblasts Promotes Gastric Cancer Metastasis Through Activating TGF-Β1 and Il-6/Stat3 Signal Pathways

Interleukin (IL)-1 Beta and IL-6 Activated Acute and Chronic Myelogenous Leukemia-Derived Myofibroblasts to Express Leukemia-Specific Transcripts

Background and Aims: We previously reported that interleukin 1-beta (IL-1-b) stimulated bone-marrow stromal myofibroblasts from normal individuals to express CD34. And, when myofibroblasts were cultured with IL-1-b and IL-6, GATA-2 and CD45 expressed. We report here that bone marrow-derived myofibroblasts from acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) patients were also activated to express leukemia-specific molecules when IL-1-b and IL-6 were added to the cultures.Materials and Methods: Bone marrow samples were collected from informed 7 AML patients (2 cases of M2 with t(8;21), 3 of M0, M2, and M7 positive for FLT-ITD mutation, 2 of Philadelphia-positive bi-phenotypic acute leukemia (Ph-AL)), and 3 CML ones, whose mononuclear cells were separated, and were cultured, split, and re-cultured for one month to eliminate non-adherent cells, vascular cells, and monocytes/macrophages to prepare myofibroblasts. The obtained cells were further cultured for one more month to obtain myofibroblasts with stably growth, and then leukemia-specific molecules (FLT3-ITD, BCR-ABL1 fusion (major and minor), RUNX1-RUNX1T1 fusion) were analyzed at DNA and RNA levels. Cells were further cultured with IL-1-b and IL-6 for two weeks, and morphological changes and expressions of specific molecules were observed.Results: When bone marrow-derived myofibroblast obtained from myeloid leukemia patients were analyzed, leukemia-specific molecules were detected at DNA levels (FISH analysis detected 0.5-5% BCR-ABL1 fusion in CML- and Ph-AL-derived myofibroblast-cultures, 1-2% RUNX1- RUNX1T1 in AML with t(8;21)-cultures, and positive FLT3-ITD mutation at genomic PCR in AML-cultures); however, RT-PCR analyses revealed that leukemia-specific transcripts were not detected in all cells. When myofibroblasts were cultured with IL-1-b and IL-6, leukemia-specific transcripts were detected with RT-PCR analysis in all cases. Also, CD45, and GATA-2 expressed in these cultures.Discussion: We reported previously that a few populations of bone marrow-derived myofibroblasts obtained from AML and CML patients expressed leukemia-specific transcripts and proteins when cultured as a separated single colony; however, when myofibroblasts were cultured not as a fractionated single colony but a whole stromal cells for a long term, expression of leukemia-specific molecules weakened and no longer confirmed. Myofibroblasts with leukemic character seem to stop their proliferation and keep dormant. One interesting point is that normal stromal myofibroblasts derived from myeloid leukemia patients can inhibit the growth of myofibroblasts that have leukemic characters. Some mechanisms may work on this observation. Also, an important issue is that myofibroblasts reportedly have an ability of antigen presentation. If some myofibroblasts can express leukemia-specific molecules as well as HLA when cultured with IL-1-b and IL-6, they can act as a leukemia-specific antigen-presenting cell. We now attempt to research this theme to develop a new cell-mediated vaccine for myeloid leukemia. DisclosuresNo relevant conflicts of interest to declare.

Liver fibrosis.

Liver fibrosis is a wound-healing response generated against an insult to the liver that causes liver injury. It has the potential to progress into cirrhosis, and if not prevented, it may lead to liver cancer and liver failure. The activation of hepatic stellate cells (HSCs) is the central event underlying liver fibrosis. In addition to HSCs, numerous studies have supported the potential contribution of bone marrow-derived cells and myofibroblasts to liver fibrosis. The liver is a heterogeneous organ; thus, molecular and cellular events that underlie liver fibrogenesis are complex. This review aims to focus on major events that occur during liver fibrogenesis. In addition, important antifibrotic therapeutic approaches and experimental liver fibrosis models will be discussed.

Targeted blockade of TGF-\u03b2 and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts

To investigate the role of TGF-β and IL-6 in myofibroblasts (MFs) — lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF-β signaling inhibitor — SB431542 and/or JAK2/STAT3 inhibitor — JSI-124. MFs were stimulated by TGF-β, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-β. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-β in cancer cells. In contrast, cancer cell-CM or TGF-β stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-β signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-β and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy.

The IL-4 receptor α has a critical role in bone marrow–derived fibroblast activation and renal fibrosis

Renal fibrosis is a common pathway leading to the progression of chronic kidney disease, and bone marrow-derived fibroblasts contribute significantly to the development of renal fibrosis. However, the signaling mechanisms underlying the activation of these fibroblasts are not completely understood. Here, we examined the role of IL-4 receptor α (IL-4Rα) in the activation of myeloid fibroblasts in two experimental models of renal fibrosis. Compared with wild-type mice, IL-4Rα knockout mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts in their kidneys. IL-4Rα deficiency suppressed the expression of α-smooth muscle actin, extracellular matrix proteins and the development of renal fibrosis. Furthermore, IL-4Rα deficiency inhibited the activation of signal transducer and activator of transcription 6 (STAT6) in the kidney. Moreover, wild-type mice engrafted with bone marrow cells from IL-4Rα knockout mice exhibited fewer myeloid fibroblasts in the kidney and displayed less severe renal fibrosis following ureteral obstructive injury compared with wild-type mice engrafted with wild-type bone marrow cells. Invitro, IL-4 activated STAT6 and stimulated expression of α-smooth muscle actin and fibronectin in mouse bone marrow monocytes. This was abolished in the absence of IL-4Rα. Thus, IL-4Rα plays an important role in bone marrow-derived fibroblast activation, resulting in extracellular matrix protein production and fibrosis development. Hence, the IL-4Rα/STAT6 signaling pathway may serve as a novel therapeutic target for chronic kidney disease.

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

Apoptosis of the Tracheal Epithelium Can Increase the Number of Recipient Bone Marrow-Derived Myofibroblasts in Allografts and Exacerbate Obliterative Bronchiolitis After Tracheal Transplantation in Mice.

The long-term outcome of lung transplantation is impeded by the development of obliterative bronchiolitis (OB). We sought to investigate the relationship between the apoptosis of tracheal epithelial cells and bone marrow-derived myofibroblasts in the process of OB. The mouse orthotopic tracheal transplant model was established. The allografts and syngrafts were harvested at 1, 2, 3, and 4 weeks after tracheal transplant. The percentage of tracheal lumen occlusion was assayed via histology and morphometry. Immunofluorescence staining was used to detect the apoptotic epithelial cells and recipient-derived myofibroblasts. The expression of SDF-1α and TGF-β and the infiltrations of CD4 and CD8 T cells in the grafts were detected using immunohistochemical staining. We found that there were more apoptotic epithelia in the allograft group than in the syngraft group and that the level of tracheal lumen occlusion was higher at different time points. Moreover, the increase in the apoptosis of the tracheal epithelium occurred earlier than that of occlusion of the tracheal lumen. There were more myofibroblasts derived from the recipient's bone marrow and more CD4 and CD8 T cells in the allografts. The expression of SDF-1α and TGF-β was higher in the epithelium from allografts than in those of the syngrafts. Our study indicated that the apoptotic tracheal epithelia in the OB model might increase the amount of myofibroblasts derived from the recipient's bone marrow. Therapeutic methods aimed at preventing apoptosis of the tracheal epithelium may improve the outcome of lung transplantation.

CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis.

Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.

Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis.

Bone marrow-derived cells play important roles in cancer development and progression. Our previous studies demonstrated that murine bone marrow-derived myofibroblasts (BMFs) enhanced tumor growth. In this study, we investigated the mechanisms of BMF actions. We found that co-injection of BMFs with gastric cancer cells markedly promoted tumorigenesis. Co-cultured BMFs or BMF-conditioned medium (BMF-CM) induced the formation of spheres, which expressed stem cell signatures and exhibited features of self-renewal, epithelial-to-mesenchymal transition and tumor initiation. Furthermore, CD44+ fractions in spheres were able to initiate tumorigenesis and reestablish tumors in serially passaged xenografts. In co-culture systems, BMFs secreted high levels of murine interleukin-6 (IL-6) and hepatocyte growth factor (HGF), while cancer cells produced high level of transformation growth factor-β1 (TGF-β1). BMF-CM and IL-6 activated BMFs to produce mHGF, which activated signal transducer and activator of transcription 3 (STAT3) and upregulated TGF-β1 in human cancer cells. In return, cancer cell-CM stimulated BMFs to produce IL-6, which was inhibited by anti-TGF-β1 neutralizing antibody. Blockade of HGF/Met, JAK2/STAT3 and TGF-β1 signaling by specific inhibitors inhibited BMF-induced sphere formation. STAT3 knockdown in cancer cells also inhibited BMF-induced sphere formation and tumorigenesis. Moreover, TGF-β1 overexpression in cancer cells was co-related with IL-6 and HGF overexpression in stromal cells in human gastric cancer tissues. Our results demonstrate that BMF-derived IL-6/HGF and cancer cell-derived TGF-β1 mediate the interactions between BMFs and gastric cancer cells, which regulate cancer stemness and promote tumorigenesis. Targeting inhibition of the interactions between BMFs and cancer cells may be a new strategy for cancer therapy.

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets.

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis.

Myofibroblasts are a main cell-type of collagen-producing cells during tissue fibrosis, but their origins remains controversial. While bone marrow-derived myofibroblasts in renal fibrosis has been reported, the cell origin and mechanisms regulating their transition into myofibroblasts remain undefined. In the present study, cell lineage tracing studies by adoptive transfer of GFP+ or dye-labelled macrophages identified that monocyte/macrophages from bone marrow can give rise to myofibroblasts via the process of macrophage-myofibroblast transition (MMT) in a mouse model of unilateral ureteric obstruction. The MMT cells were a major source of collagen-producing fibroblasts in the fibrosing kidney, accounting for more than 60% of α-SMA+ myofibroblasts. The MMT process occurred predominantly within M2-type macrophages and was regulated by TGF-β/Smad3 signalling as deletion of Smad3 in the bone marrow compartment of GFP+ chimeric mice prevented the M2 macrophage transition into the MMT cells and progressive renal fibrosis. In vitro studies in Smad3 null bone marrow macrophages also showed that Smad3 was required for TGF-β1-induced MMT and collagen production. In conclusion, we have demonstrated that bone marrow-derived fibroblasts originate from the monocyte/macrophage population via a process of MMT. This process contributes to progressive renal tissue fibrosis and is regulated by TGF-β/Smad3 signalling.