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PubMed2005

Gene therapy progress and prospects: stem cell plasticity.

With the identification of stem cell plasticity several years ago, multiple reports raised hopes that tissue repair by stem cell transplantation could be within reach in the near future. Krause et al reported that a single purified hematopoietic stem cell not only repopulated the bone marrow of a host animal, but also integrated into unrelated tissues. Lagasse et al demonstrated that in a genetic model of liver disease, purified hematopoietic stem cells can give rise to hepatocytes and rescue fatal liver damage. More recent work by Jiang et al demonstrated that cultured cells can retain their stem cell potential. There are a number of possible mechanisms that could explain these phenomena, and recent experiments have raised controversy about which mechanism is prevalent. One possibility is transdifferentiation of a committed cell directly into another cell type as a response to environmental cues. Transdifferentiation has been shown mainly in vitro, but some in vivo data also support this mechanism. Direct transdifferentiation would clinically be limited by the number of cells that can be introduced into an organ without removal of resident cells. If bone marrow cells could on the other hand give rise to stem cells of another tissue, then they could in theory repopulate whole organs from a few starting cells. This model of dedifferentiation is consistent with recent data from animal models. Genetic analysis of cells of donor origin in vivo and in vitro has brought to light another possible mechanism. The fusion of host and donor cells can give rise to mature tissue cells without trans- or dedifferentiation. The resulting heterokaryons are able to cure a lethal genetic defect and do not seem to be prone to give rise to cancer. All these models will clinically face the problem of accessibility of healthy primary cells for transplantation. This underlines the importance of the recent identification of a population of mesenchymal stem cells (MSCs) with stem cell properties similar to embryonic stem (ES) cells. These cells can be cultured and expanded in vitro without losing their stem cell potential making them an attractive target for cell therapy. Finally, it is still not clear if stem cells for various tissues are present in peripheral blood, or bone marrow and thus can be directly purified from these sources. Identification of putative tissue stem cells would be necessary before purification strategies can be devised. In this review, we discuss the evidence for these models, and the conflicting results obtained to date.

Animals↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2005

Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms.

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16alpha-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR-/-) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR-/--derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

Animals↗
PubMed2001

Cell type proportioning in Dictyostelium slugs: lack of regulation within a 2.5-fold tolerance range.

The proportion of prestalk and prespore cells in Dictyostelium discoideum slugs is often cited as an example of "almost perfect" regulation. The pattern is similar over a very wide range of cell number; furthermore, removal of either of the cell types leads to compensatory transdifferentiation. Several studies of Dictyostelium fruiting bodies, however, have suggested that proportioning in Dictyostelium differs systematically from true constancy. We have confirmed this in the slug stage using a short-lived beta-galactosidase as a reporter of the prestalk specific ecmA gene expression: the prestalk proportion decreases from 24+/-5% in slugs of 10(3) cells to 10+/-3% when 10(5) cells are present. Regeneration experiments suggest that this difference is not due to a modulation of the proportioning set-point by size, as one might have expected; instead there appears to be a regulatory "tolerance zone" at all sizes. After amputation of the whole posterior region, transdifferentiation stops after the fraction of prestalk has been reduced from 100% to 28+/-20%, well above the initial value of 10+/-3%, while after anterior removal the transdifferentiation endpoint is about 10%. Most strikingly, we find no regulation at all after partial amputations of the prespore region. It seems that any prestalk proportion is stable between a approximately 10% lower threshold and a approximately 30% upper threshold. To explain this, we propose a regulation mechanism based on a negative feedback plus cell type bistability. In both intact and regenerating slugs we find that the slug morphology is regulated so that the length-to-width ratio of the anterior region is constant.

Amputation, Surgical↗
PubMed2003

Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy.

BACKGROUND: The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury. METHODS: Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining. RESULTS: ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation. CONCLUSION: Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.

Angiotensin II↗
PubMed2002

Regulation of endothelin-A receptor sensitivity by cyclic adenosine monophosphate in rat hepatic stellate cells.

Sensitization of the endothelin-A receptor (ET(A)) occurs during HSC transdifferentiation, but the underlying mechanisms remained unclear. Sensitization of ET(A) was studied in quiescent and activated hepatic stellate cells (HSC) at the levels of receptor phosphorylation, localization, endothelin (ET)-1-induced Ca(2+) signals, and cell contraction. The endothelin-1 (ET-1) concentrations required to obtain an ET(A)-mediated Ca(2+) signal in 50% of HSC cultured for 1 to 2 or 10 days were approximately 1.2 and 0.012 nmol/L, respectively. This transdifferentiation-dependent sensitization of ET(A) was accompanied by receptor translocation to the plasma membrane. Cyclic AMP rapidly desensitized ET(A) in activated HSC and shifted their ET-1 responsiveness from picomolar to nanomolar concentrations with respect to Ca(2+) signals and HSC contraction. ET(A) desensitization also occurred in response to prostaglandin E(2), adenosine, or ET(B) stimulation. Desensitization by cAMP in activated HSC was accompanied by an increased Ser/Thr phosphorylation of ET(A) and their rapid internalization. Quiescent HSC exhibited Ser/Thr phosphorylation of the ET(A) protein, which was not affected by cAMP. In conclusion, the ET(A) response in HSC is regulated by protein kinase A (PKA)-dependent receptor phosphorylation and internalization. This may explain the transdifferentiation-dependent sensitization of HSC towards ET-1 and its reversal by cAMP and ET(B) activation.

Animals↗
PubMed2003

p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts.

Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB)-phenotype on plastic dishes. This response recapitulates the features of activation in vivo. Transforming growth factor beta (TGF-beta) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF-beta signaling involves TGF-beta type I receptor (TbetaRI)-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogen-activated protein kinase (MAPK). This study elucidates the change of Smad3-mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C-terminal region and the phosphorylated linker region of Smad3, we found that TGF-beta-dependent Smad3 phosphorylation at the C-terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF-beta activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero-complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TbetaRI-phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor-type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TbetaRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK-dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in vivo.

Active Transport, Cell Nucleus↗
PubMed2004

[Effect of growth factors on the differentiation of porcine lens epithelial cells].

BACKGROUND: Besides cell proliferation, transdifferentiation of lens epithelial cells (LECs) to myofibroblasts is one of the mechanisms of secondary cataract formation. This process is characterized by increased expression of alpha-smooth muscle actin (alpha-SMA). This study investigated the influence of bFGF, TGF-beta2, EGF and IGF-1 on the expression of alpha-SMA in porcine LECs. MATERIALS AND METHODS: Porcine LECs were cultured for 7 days in serum-free medium without or with 1 to 50 ng/ml bFGF, TGF-beta2, EGF or IGF-I. Alpha-SMA was detected immunocytochemically with a mouse monoclonal antibody, and the relative numbers of alpha-SMA-positive cells were calculated. Statistical analysis was performed using Student's unpaired t-test. RESULTS: The ratio of alpha-SMA-positive cells cultured for 7 days in serum-free medium was 36 +/- 11.9 % (mean +/- SD). BFGF significantly reduced this ratio in a dose-dependent manner to 11.2 +/- 7.3 % at a concentration of 50 ng/ml (p < 0.0001). EGF reduced the ratio significantly to 25.1 +/- 15.7 % (p = 0.05) when 50 ng/ml were applied. IGF-1 (10 ng/ml) reduced the relative numbers of transdifferentiated cells to 16.8 +/- 5.8 %, but the reduction was not statistically significant (p = 0.0787). TGF-beta2 (50 ng/ml) slightly increased the relative number of alpha-SMA-positive cells to 44.2 +/- 13.8 %. However, this increase was not significant (p = 0.1202) during a culture period of 7 days. CONCLUSIONS: BFGF and EGF significantly reduced the expression of alpha-SMA by LECs while TGF-beta and IGF-1 had no statistically significant effect. These results suggest that bFGF and EGF do not primarily induce secondary cataract formation by the mechanism of cell transdifferentiation.

Actins↗
PubMed2005

Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells.

Although several studies have suggested that insulin-secreting cells can be generated in vitro from cells residing in adult exocrine pancreas, neither the origin of these cells nor their precise insulin secretory properties was obtained. We show here that insulin-secreting cells can be derived from adult mouse pancreatic exocrine cells by suspension culture in the presence of EGF and nicotinamide. The frequency of insulin-positive cells was only 0.01% in the initial preparation and increased to approximately 5% in the culture conditions. Analysis by the Cre/loxP-based direct cell lineage tracing system indicates that these newly made cells originate from amylase/elastase-expressing pancreatic acinar cells. Insulin secretion is stimulated by glucose, sulfonylurea, and carbachol, and potentiation by glucagon-like peptide-1 also occurs. Insulin-containing secretory granules are present in these cells. In addition, we found that the enzymatic dissociation of pancreatic acini itself leads to activation of EGF signaling, and that inhibition of EGF receptor kinase blocks the transdifferentiation. These data demonstrate that pancreatic acinar cells can transdifferentiate into insulin-secreting cells with secretory properties similar to those of native pancreatic beta cells, and that activation of EGF signaling is required in such transdifferentiation.

Animals↗
PubMed2006

Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins.

Activated hepatic stellate cells (HSC) that transdifferentiate to myofibroblasts in the injured liver are responsible for scar formation that leads to fibrosis and eventually cirrhosis. To investigate the gene expression profile during different stages of this process, we performed serial analysis of gene expression, representing a quantitative and qualitative description of all expressed genes. Stellate cells were isolated from human livers and cultured. Serial analysis of gene expression was performed on RNA isolated from quiescent, activated, and transdifferentiated HSC. Comparison of the three resulting transcriptomes showed that less than 5% of all genes changed significantly in expression. Established markers of liver fibrosis showed enhanced expression in accordance with the transdifferentiation process. In addition, induction was seen for several genes not yet recognized to be involved in liver fibrosis, such as insulin-like growth factor-binding proteins (IGFBP) and antagonists of bone morphogenic proteins: follistatin and gremlin. The induction of these genes was validated in vivo in mice developing liver fibrosis. The expression of IGFBPs and gremlin was measurable in the livers of these mice, whereas it was low or undetectable in control mice without liver fibrosis. Since gremlin modulates the activity of bone morphogenic growth factors, it may represent a novel pathway and a target for therapeutic intervention and together with IGFBPs it could be a specific marker of liver fibrosis. In conclusion, the comparison of the three transcriptomes of (activated) stellate cells reveals novel genes involved in fibrogenesis and provides an appreciation of the sequence and timing of the fibrotic process in liver.

Animals↗
PubMed2003

Tissue macrophages: "satellite cells" for growing collateral vessels? A hypothesis.

It has been demonstrated in several studies that collateral growth is associated with accumulation of macrophages around proliferating vessel. Macrophages are known to secrete vascular growth factors and metalloproteinases. Both are necessary for the development of a proper vasculature. Recent studies suggest that certain subpopulations of macrophages are also capable of transdifferentiating into vascular cells. There are good reasons to assume that shear force rises dramatically in preexisting arteriolar shunts after occlusion of the main supplying vessel. Based upon these two findings it was hypothesized that high shear forces lead to homing of circulating monocytes to the growing collateral artery. The majority of studies, however, indicate that monocytes home under low shear force conditions. Our own observations in monocyte depleted animals suggest that proliferation and transdifferentiation of tissue macrophages occurs locally in growing collateral vessels and is independent of circulating cells. We thus propose that local proliferation and transdifferentiation of tissue macrophages rather than homing of circulating monocytes play a major role in arteriogenesis.

Arteries↗
PubMed2004

Development of respiratory stem cells and progenitor cells.

Research of stem cells has caught much attention in the past few years with its promise for therapeutic and regenerative applications in a variety of diseases and organ systems. The latest studies have also urged us to understand further the somatic stem cell plasticity or transdifferentiation capability. More vigorous research is urgently required to verify whether or not bone marrow stem cells can differentiate into a variety of cell types in different organs including heart, liver, lung, and so forth. The lung employs a myriad of cell phenotypes in its unique function of inhaling and expiring air. Due to this structural complexity, transdifferentiation of stem cells into the lung is particularly complicated. In addition, assessing the stem cells and lung progenitor cells in the respiratory system is technically difficult. Despite these difficulties, recent studies have advanced our understanding of bone marrow stem cells differentiating into lung progenitors as well as characteristics of the local progenitor cells. This review will briefly discuss the current state of research of stem cell transdifferentiation and development, with a focus on the obstacles that limit use of stem cells in lung regeneration.

Animals↗
PubMed2006

Suppression of disease phenotypes of adult mito-mice carrying pathogenic mtDNA by bone marrow transplantation.

For directly addressing the issue of gene therapy of adult patients with mitochondrial diseases, we carried out bone marrow transplantation to adult mito-mice with mutated mtDNA and expressing respiration defects for improvement of disease phenotypes. We supposed that bone marrow cells transdifferentiated into various tissues, so that their transplantation would suppress disease phenotypes. The results showed improvement of survival and delayed expression of renal failure. As most mito-mice without a transplant died due to renal failure, we examined whether transplanted bone marrow cells transdifferentiated into renal tissues carrying improved renal function. Histochemical analyses showed that the suppression of disease phenotypes was not due to transdifferentiation, but due to suppression of apoptosis of renal cells. Thus, bone marrow cells possess a novel function of supporting tissues by suppressing apoptosis induced by respiration defects.

Animals↗
PubMed1990

Tissue- and species-specific promoter elements of rat gamma-crystallin genes.

The 5' flanking regions of the six rat gamma-crystallin genes (gamma A-gamma F) are all capable of conferring lens-specific expression to the bacterial chloramphenicol acetyl transferase (CAT) reporter gene in either transdifferentiating chicken neural retina cells or mouse lens epithelial cells. Deletion mapping of the most active gamma-crystallin promoter region, the gamma D region, showed that at least three elements are required for maximal expression in mouse lens epithelial cells: element(s) located between -200 and -106, a conserved CG rich region around position -75, and a CG stretch around -15. The region between -200 and -106 was dispensable in transdifferentiating chicken neural retina cells, which instead required the region between -106 and -78. The maximal activity of the gamma E and gamma F promoters was also dependent upon the integrity of the conserved CG region located around -75. A synthetic oligonucleotide containing this sequence was capable of lens-specific enhancement of the activity of the tk promoter in transdifferentiating chicken neural retina cells but not in mouse lens epithelial cells. Our results further show that this region may contain a silencer element, active in non-lens tissues, as well.

Animals↗
PubMed2002

Analysis of early processes in wound-induced vascular regeneration using TED3 and ZeHB3 as molecular markers.

Interruption of the vascular bundles of Zinnia internodes induced transdifferentiation of cells into tracheary elements (TEs) or sieve elements (SEs) within 4 d of wounding. The early stage of the regeneration processes was analyzed using two molecular marker genes, TED3 and ZeHB3, which are expressed specifically in TE precursor cells and immature phloem cells, respectively. An increase in the numbers of TED3 and ZeHB3 mRNA-expressing cells always preceded an increase in the numbers of TEs and SEs formed. The earliest sign of vascular differentiation was the appearance 24 h after wounding of a layer(s) of TED3 mRNA-expressing cells in the inter- and intrafascicular cambial-like regions along the severed vascular bundles. In contrast, the number of ZeHB3 mRNA-expressing cells decreased dramatically along the severed bundles 24 h after wounding, and increased again 36 h after wounding. These results clearly indicate that xylem and phloem differentiation are not synchronized during vascular regeneration. Treatment with 10(-3) M colchicine abolished the expression of ZeHB3 mRNA in pith parenchyma, but not TED3 mRNA; this suggests that cell division is a prerequisite for the transdifferentiation of pith parenchymal cells into immature phloem cells expressing ZeHB3. In contrast, transdifferentiation of pith parenchymal cells to TE precursor cells does not require preceding cell division. However, the inhibition of cell division prevented the formation of both radial files of TEs and the cambial-like layer(s) of TED3 mRNA-expressing cells, and, ultimately, vascular regeneration altogether. These results imply that wound-induced cambial-like activity in and between severed vascular bundles is essential for vascular regeneration.

Asteraceae↗
PubMed2005

Are there any stem cells in the pancreas?

A vast number of studies indicate the presence of stem/progenitor cells virtually in all tissues in adult organs, particularly in bone marrow. Recent studies, however, cast doubt about the existence of true stem cells in adult tissue. The complex integrity of several cells with distinct morphologic and functional properties in the mature pancreas confers an appropriate status for stem cell research. Several different types of cells residing in the islets or in the ductal epithelium have been proposed as adult pancreatic stem cells or progenitor cells. However, these reports do not provide conceivable proof for the presence of true pancreatic stem cells. On the other hand, there is considerable evidence indicating transdifferentiation of all adult pancreatic cells into each other, and under proper conditions, to nonpancreatic cells including oncocytes and hepatocytes. Observations pertaining to the putative pancreatic stem cells, transdifferentiation ability of the differentiated mature pancreatic cells in the normal and diseased pancreas will be discussed, and our own findings supporting the transdifferentiation pathway are presented in this article.

Animals↗
PubMed2005

Mutual paracrine effects of colorectal tumour cells and stromal cells: modulation of tumour and stromal cell differentiation and extracellular matrix component production in culture.

Interactions of tumour and stromal cells influence tumour cell proliferation and differentiation, stromal cell phenotypic transdifferentiation and secretion of extracellular matrix (ECM) components. In this study, we established a monolayer and a three-dimensional cell-to-cell interaction model between canine mammary stromal cells and human colonic carcinoma cell lines (Caco-2 and HT-29) to investigate mutual paracrine effects of tumour cells and stromal cells on (i) tumour cell differentiation, (ii) production of ECM components and (iii) phenotypic transdifferentiation of stromal cells. We showed that when Caco-2 or HT-29 cells are cultured in collagen gels, they form a few small solid cell clusters with no lumina, but when cocultured with stromal cells, the tumour cells formed glandular structures with central lumina. This fibroblast-induced organization and differentiation of Caco-2 cells (not HT-29 cells) appeared to be mediated by transforming growth factor-beta (TGF-beta). Culturing of stromal cells, Caco-2 cells or HT-29 cells alone in both monolayers and gels resulted in weak tenascin-C expression in stromal cells and HT-29 cells and no expression in the Caco-2 cells. Coculturing of stromal cells with tumour cells resulted in increased tenascin-C expression in the stromal cells and HT-29 cells and induced expression of tenascin-C in the Caco-2 cells. This induction and increased expression of tenascin-C appeared to be mediated by TGF-beta. Culturing of stromal cells, Caco-2 cells or HT-29 cells alone on monolayers and in gels resulted in a weak expression of chondroitin sulfate (CS), chondroitin-6-sulfate (C-6-S) and versican in stromal cells and no expression in Caco-2 and HT-29 cells. Coculturing of stromal cells with tumour cells on monolayers and in gels resulted in increased CS, C-6-S and versican expression in stromal cells. This tumour cell-induced expression of CS, C-6-S and versican appeared to be mediated by TGF-beta and platelet-derived growth factor (PDGF). Coculturing of Caco-2 and HT-29 and stromal cells promoted the transdifferentiation of stromal cells into myofibroblasts, and this appeared to be mediated by TGF-beta. These results suggest that TGF-beta and PDGF are part of a paracrine system involved in stromal-epithelial cell interaction important in stromal cell differentiation and ECM component production.

Actins↗
PubMed2006

Cellular inflammatory response to persistent localized Staphylococcus aureus infection: phenotypical and functional characterization of polymorphonuclear neutrophils (PMN).

Persistent, localized Staphylococcus aureus infections, refractory to antibiotic treatment, can result in massive tissue destruction and surgical intervention is often the only therapeutic option. In that context, we investigated patients with S. aureus-induced infection at various sites, apparent as either olecranon bursitis, empyema of the knee joint or soft tissue abscess formation. As expected, a prominent leucocyte infiltrate was found, consisting predominantly of polymorphonuclear neutrophils (PMN) (up to 75%) and to a lesser extent of T lymphocytes and natural killer (NK) cells. In line with their bactericidal capacity, PMN expressed the high-affinity receptor for IgG, CD64 and the lipopolysaccharide (LPS) receptor CD14; moreover, the oxygen radical production in response to the bacterial peptide f-MLP was enhanced, while chemotactic activity was greatly reduced. The more intriguing finding, however, was that a portion of PMN had acquired major histocompatibility complex (MHC) class II antigens and CD83, indicative of a transdifferentiation of PMN to cells with dendritic-like characteristics. Of note is that a similar transdifferentiation can be induced in PMN in vitro, e.g. by gamma interferon or by tumour necrosis factor alpha. Co-cultivation of transdifferentiated PMN with autologous T lymphocytes resulted in prominent T cell proliferation, provided that S. aureus enterotoxin A was added. Taken together, persistent S. aureus infection induces PMN to acquire characteristics of dendritic cells, which in turn might promote the local immune response.

Aged↗