Cellular origin of Kaposi&apos;s sarcoma and Kaposi&apos;s sarcoma-associated herpesvirus-induced cell reprogramming

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Abstract

Kaposi's sarcoma (KS) is the most common malignancy in untreated HIV patients. KS is characterised by abnormal neoangiogenesis, inflammation, and proliferation of tumour cells [KS spindle cells (SCs)]. Kaposi's sarcoma-associated herpesvirus (KSHV) is the aetiological agent of KS. KS SCs are the predominant KSHV-infected cells in KS lesions. In this review, we report advances in understanding of the cellular origin of the KS SC, a contentious topic in KSHV research. KS SCs are now known to be of endothelial cell (EC) origin, phenotypically most similar to lymphatic ECs (LECs), but poorly differentiated. We focus on recent insights into KSHV's ability to exploit the normal differentiation pathway and intrinsic plasticity of ECs, through manipulation of EC-specific transcriptional regulators [i.e., prospero homeobox 1 (PROX1) and MAF] and discuss how this may contribute to viral persistence and KS sarcomagenesis. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

Kazutoshi Takahashi, Shinya Yamanaka (2006)

Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.

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Direct conversion of fibroblasts to functional neurons by defined factors

Thomas Vierbuchen, Austin Ostermeier, Zhiping Pang … (2010)

Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2, and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine.

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In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.

Qiao Zhou, Juliana R Brown, Andrew Kanarek … (2008)

One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble beta-cells. The induced beta-cells are indistinguishable from endogenous islet beta-cells in size, shape and ultrastructure. They express genes essential for beta-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.