We used rat experimental myocardial infarction to study the ultrastructural recovery, especially neo-angiogenesis in the infarction border zone. We were interested in the possible role(s) of telocytes (TCs), a novel type of interstitial cell very recently discovered in myocardim (see ). Electron microscopy, immunocytochemistry and analysis of several proangiogenic microRNAs provided evidence for TC involvement in neo-angiogenesis after myocardial infarction. Electron microscopy showed the close spatial association of TCs with neoangiogenetic elements. Higher resolution images provided the following information: (a) the intercellular space between the abluminal face of endothelium and its surrounding TCs is frequently less than 50 nm; (b) TCs establish multiple direct nanocontacts with endothelial cells, where the extracellular space seems obliterated; such nanocontacts have a length of 0.4–1.5 μm; (c) the absence of basal membrane on the abluminal face of endothelial cell. Besides the physical contacts (either nanoscopic or microscopic) TCs presumably contribute to neo-angiognesis via paracrine secretion (as shown by immunocytochemistry for VEGF or NOS2). Last but not least, TCs contain measurable quantities of angiogenic microRNAs (e.g. let-7e, 10a, 21, 27b, 100, 126-3p, 130a, 143, 155, 503). Taken together, the direct (physical) contact of TCs with endothelial tubes, as well as the indirect (chemical) positive influence within the ‘angiogenic zones’, suggests an important participation of TCs in neo-angiogenesis during the late stage of myocardial infarction.

BCL11 genes play crucial roles in lymphopoiesis and have been associated with hematopoietic malignancies. Specifically, disruption of the BCL11B (B-cell chronic lymphocytic leukemia/lymphoma 11B) locus is linked to T-cell acute lymphoblastic leukemia, and the loss of heterozygosity in mice results in T-cell lymphoma. BCL11 proteins are related C 2 H 2 zinc-finger transcription factors that act as transcriptional repressors. Here, we demonstrate the association of the endogenous BCL11B with the nucleosome remodeling and histone deacetylase (NuRD) complex, one of the major transcriptional corepressor complexes in mammalian cells. BCL11B complexes from T lymphocytes possess trichostatin A-sensitive histone deacetylase activity, confirming the functionality of the complexes. Analysis of the BCL11B-NuRD association demonstrated that BCL11B directly interacted with the metastasis-associated proteins MTA1 and MTA2 through the amino-terminal region. We provide evidence for the functional requirement of MTA1 in transcriptional repression mediated by BCL11B through the following: (1) overexpression of MTA1 enhanced the transcriptional repression mediated by BCL11B, (2) knockdown of MTA1 expression by small interfering RNA inhibited BCL11B transcriptional repression activity and (3) MTA1 was specifically recruited to a BCL11B targeted promoter. Taken together, these data support the hypothesis that the NuRD complex mediates transcriptional repression function of BCL11B.

Telocytes (TCs) are interstitial cells with telopodes – very long prolongations that establish intercellular contacts with various types of cells. Telocytes have been found in many organs and various species and have been characterized ultrastructurally, immunophenotypically and electrophysiologically (http://www.telocytes.com). Telocytes are distributed through organ stroma forming a three-dimensional network in close contacts with blood vessels, nerve bundles and cells of the local immune system. Moreover, it has been shown that TCs express a broad range of microRNAs, such as pro-angiogenic and stromal-specific miRs. In this study, the gene expression profile of murine lung TCs is compared with other differentiated interstitial cells (fibroblasts) and with stromal stem/progenitor cells. More than 2000 and 4000 genes were found up- or down-regulated, respectively, in TCs as compared with either MSCs or fibroblasts. Several components or regulators of the vascular basement membrane are highly expressed in TCs, such as Nidogen, Collagen type IV and Tissue Inhibitor of Metalloproteinase 3 (TIMP3). Given that TCs locate in close vicinity of small vessels and capillaries, the data suggest the implication of TCs in vascular branching. Telocytes express also matrix metalloproteases Mmp3 and Mmp10, and thus could regulate extracellular matrix during vascular branching and de novo vessel formation. In conclusion, our data show that TCs are not fibroblasts, as the ultrastructure, immunocytochemistry and microRNA assay previously indicated. Gene expression profile demonstrates that TCs are functionally distinct interstitial cells with specific roles in cell signalling, tissue remodelling and angiogenesis.

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Telocytes (TCs) are a particular type of interstitial (stromal) cells defined by very long, moniliform telopodes. Their tissue location, between blood vessels and other cells such as cardiomyocytes (CMC) and neurons, suggests a role in intercellular signalling. In order to define a microRNA (miR) signature in cardiac TCs, we have found that miR-193 is differentially expressed between TCs and other interstitial cells. Because miR-193 regulates c-kit, our data support the previous finding that TCs express c-kit in certain circumstances. In addition, the miRs which are specific to CMC and other muscle cells (e.g. miR-133a, miR-208a) are absent in TCs. Overall the data reinforce the view that TCs are a particular type of interstitial (mesenchymal) cells.

Telocytes (TCs) are cells ubiquitously distributed in the body and characterized by very long and thin prolongations named telopodes (Tps). Cardiac TCs are the best characterized TCs for the moment. Tps release extracellular vesicles (EVs) in vivo and in vitro suggesting that TCs regulate the activity of other cells by vesicular paracrine signals. TCs have been found within the stem cell niche of several organs. Electron microscopy or electron tomography has shown that Tps are located in close vicinity of stem cells (SC). Since stem cell regulation by niche components involves paracrine signalling, we have investigated if TCs could be part of this mechanism. Using fluorescent labelling of cells and EVs with calcein and Cy5-miR-21 oligos, we provide evidence that TCs can modulate SC through EVs loaded with microRNAs. TCs deliver microRNA to cardiac stem cells (CSCs), as well as to other types of SCs (e.g. hematopoietic SC) indicating that this mechanism is not restricted to cardiac tissue. We also found that CSCs deliver microRNA loaded EVs to TCs, suggesting that there is a continuous, post-transcriptional regulatory signal back and forth between TCs and SC. In conclusion, our data reveal the existence of a reciprocal (bidirectional) epigenetic signalling between TCs and SC.

The MAM (meprin/A5-protein/PTPmu) domain is present in numerous proteins with diverse functions. PTP belongs to the MAM-containing subclass of protein-tyrosine phosphatases (PTP) able to promote cell-to-cell adhesion. Here we provide experimental evidence that the MAM domain is a homophilic binding site of PTP. We demonstrate that the MAM domain forms oligomers in solution and binds to the PTP ectodomain at the cell surface. The presence of two disulfide bridges in the MAM molecule was evidenced and their integrity was found to be essential for MAM homophilic interaction. Our data also indicate that PTP ectodomain forms oligomers and mediates the cellular adhesion, even in the absence of MAM domain homophilic binding. Reciprocally, MAM is able to interact homophilically in the absence of ectodomain trans binding. The MAM domain therefore contains independent cis and trans interaction sites and we predict that its main role is to promote lateral dimerization of PTP at the cell surface. This finding contributes to the understanding of the signal transduction mechanism in MAM-containing PTPs.The phosphorylation state of numerous signaling proteins is controlled by opposing activities of protein-tyrosine kinases and protein-tyrosine phosphatases (PTP) 1 (1). The family of PTPs consists of soluble and receptor-like PTPs (RPTPs) (2). Whereas the intracellular region of RPTPs is relatively similar in all representatives containing either a single or two PTP domains, the extracellular region has a large diversity. PTP belongs to subclass IIB, called "MAM-containing PTP" (2). Besides the MAM domain (meprin/A5-protein/PTPmu domain; Ref.3), their extracellular region contains a single immunoglobulin (Ig)-like domain and four fibronectin (FN) III repeats (4). This structural architecture of ectodomain is similar to members of the cell-adhesion molecule superfamily.PTP is strongly expressed in the endothelial cell layer of the arteries and continuous capillaries as well as in cardiac muscle, bronchial and lung epithelia, retina, and several brain areas (4 -6). At the subcellular level, it is localized at sites of cell-cell contact (7). In this regard, it has been demonstrated that PTP restores E-cadherin-mediated cellular adhesion, when it is expressed in LNCaP human prostate carcinoma cells (8). Physiologically, PTP has been shown to be involved in promotion and regulation of neurite outgrowth (5, 9).Numerous experiments have clearly demonstrated that the extracellular region of PTP promotes cell-cell aggregation in a Ca 2ϩ -independent manner (10, 11). The homophilic binding has been also evidenced in the ectodomains of PTP (12) and PTP (13), strongly suggesting that these RPTPs may be involved in signal transduction through cell-to-cell contact in vivo. Evidence concerning the physiological role of PTP-mediated homophilic binding has been reported in a recent article (14) showing that homophilic interactions trigger rearrangements of the axonal growth cone. However, the molecular mechanism of this interaction remains larg...

In this study we provide evidence that the transcription factor BCL11B represses expression from the HIV-1 long terminal repeat (LTR) in T lymphocytes through direct association with the HIV-1 LTR. We also demonstrate that the NuRD corepressor complex mediates BCL11B transcriptional repression of the HIV-1 LTR. In addition, BCL11B and the NuRD complex repressed TAT-mediated transactivation of the HIV-1 LTR in T lymphocytes, pointing to a potential role in initiation of silencing. In support of all the above results, we demonstrate that BCL11B affects HIV-1 replication and virus production, most likely by blocking LTR transcriptional activity. BCL11B showed specific repression for the HIV-1 LTR sequences isolated from seven different HIV-1 subtypes, demonstrating that it is a general transcriptional repressor for all LTRs.