CONTROL OF SCHWANN CELL GROWTH

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We propose continuation of studies of the regulation of Schwann cell proliferation during development, and in response to injury. Our precedent work has shown that 1) an axonal surface component stimulates Schwann cell proliferation by direct contact between cell surfaces, 2) this axonal mitogen contains a heparan sulfate proteoglycan as an essential component, 3) mitogen activity can become dissociated from its proteoglycan component during purification, 4) Schwann cells release components which can stimulate Schwann cell proliferation, and 5) substrate bound materials (especially laminin) are effective, in the presence of serum, in stimulating Schwann cell proliferation. We present a hypothesis to explain how these observations may be interrelated which proposes that the axonal surface proteoglycan may be a mitogen presenter for the Schwann cell, and that the mitogen receptor on the Schwann cell surface may be closely related to a laminin receptor. We present plans for experiments to test this hypothesis, as well as other experiments designed to explain how the Schwann cell, when fully differentiated, becomes refractory to mitogenic stimulation. The questions these experiments address include 1) Is the axonal mitogen rendered less effective with maturation by materials released from Schwann cells? 2) Is the myelin supporting Schwann cell capable of proliferation while maintaining its myelin supporting role? Why are non-myelinating Schwann cells relatively non-proliferative during Wallarian degeneration, and what manipulation will cause them to proliferate? 3) By what mechanisms do Schwann cells contribute to regulation of their own proliferation? 4) What soluble factors (and substrate bound factors) do Schwann cells release which drive Schwann cell proliferation in the absence of axons? 5) What is the nature of the mitogen receptor on the Schwann cell surface; is it linked to the mitogen receptor? 6) Will methods effective in expanding populations of primary Schwann cells in rodents be useful in expanding primary populations of Schwann cells from primates and humans? We believe that a better understanding of the interactions between axon/Schwann cell/extracellular matrix operative to regulate Schwann cell proliferation will be vital to understanding processes involving abnormalities of Schwann cell proliferation as seen in neurofibromatosis, as well as in learning how to obtain adequate numbers of Schwann cells with which to construct cellular prostheses useful in fostering regeneration in the PNS and CNS.