Trafficking and secretion of matrix metalloproteinase-2 in olfactory ensheathing glial cells: A role in cell migration?

Olfactory ensheathing cells (OECs) are unique glia found only in the olfactory system. They retain exceptional plasticity and support olfactory neurogenesis and retargeting across the PNS:CNS boundary in the olfactory system. OECs have been shown to improve functional outcome when transplanted into rodents with spinal cord injury. The growth-promoting properties of implanted OECs encompass their ability to migrate through the scar tissue and render it more permissive for axonal outgrowth, but the underlying molecular mechanisms remain poorly understood. OECs appear to regulate molecules of the extracellular matrix (ECM) that inhibit axonal growth. Among the proteins that have the potential to promote cell migration, axonal regeneration and remodeling of the ECM are matrix metalloproteinases (MMPs), a family of endopeptidases that cleave matrix, soluble, and membrane-bound proteins and that are regulated by their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs). Little is known about MMP/TIMP trafficking, secretion, and role in OECs. Using a combination of cell biology, biochemistry, pharmacology, and imaging techniques, we show that MMP-2 and MMP-9 are expressed and proteolytically active in the olfactory epithelium and in particular in the OECs of the lamina propria. These proteinases and regulatory proteins such as MT1-MMP and TIMP-2 are expressed in cultured OECs. MMPs exhibit nuclear localization and vesicular trafficking and secretion, with distribution along microtubules and microfilaments and co-localization with the molecular motor protein kinesin. Finally, we show that MMPs are involved in migration of OECs in vitro on different ECM substrates.