Regulators of human adipose-derived stem cell self-renewal.

Adipose tissue is an alternative source of mesenchymal stem cells and human adipose-derived stem cells (ASCs) display an attractive and substantial therapeutic potential when transplanted in animal models. To this end, an understanding of ASC biology is necessary and the knowledge of mechanisms that maintain ASCs in an undifferentiated state with no loss of differentiation potential during ex vivo expansion represents a crucial step. However, these mechanisms remain to be identified because appropriate human cellular models are scant. In this review we will describe a cellular model isolated from human adipose tissue displaying all the features of stem cells. Then, we will focus on the identification of intrinsic and extrinsic factors regulating the balance between human ASC proliferation and differentiation. We will point out the role of factors secreted by undifferentiated ASCs, such a FGF2, activin A, BMP4, Hedgehog molecules and secreted by adipose tissue macrophages. Finally, we will outline the role of miRNAs in these processes.

ASIC3, a sensor of acidic and primary inflammatory pain.

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular acidosis that are expressed in both central and peripheral nervous systems. Although peripheral ASICs seem to be natural sensors of acidic pain (e.g., in inflammation, ischaemia, lesions or tumours), a direct demonstration is still lacking. We show that approximately 60% of rat cutaneous sensory neurons express ASIC3-like currents. Native as well as recombinant ASIC3 respond synergistically to three different inflammatory signals that are slight acidifications (approximately pH 7.0), hypertonicity and arachidonic acid (AA). Moderate pH, alone or in combination with hypertonicity and AA, increases nociceptors excitability and produces pain suppressed by the toxin APETx2, a specific blocker of ASIC3. Both APETx2 and the in vivo knockdown of ASIC3 with a specific siRNA also have potent analgesic effects against primary inflammation-induced hyperalgesia in rat. Peripheral ASIC3 channels are thus essential sensors of acidic pain and integrators of molecular signals produced during inflammation where they contribute to primary hyperalgesia.