Electrical stimulation induces calcium-dependent release of ngf from cultured schwann cells

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Electrical Stimulation Induces Calcium-Dependent
Release of NGF From Cultured Schwann Cells
JINGHUI HUANG,1 ZHENGXU YE,1 XUEYU HU,1 LEI LU,2
AND ZHUOJING LUO1*
1Department of Spine Surgery, Institute of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
2Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University,Xi’an, China
KEY WORDS
nerve growth factor; Schwann cell; electrical stimulation;
calcium; nerve injuries
ABSTRACT
Production of nerve growth factor (NGF) from Schwann
cells (SCs) progressively declines in the distal stump, if axonal
regeneration is staggered across the suture site after
peripheral nerve injuries. This may be an important factor
limiting the outcome of nerve injuryrepair. Thus far, extensive
efforts are devoted to modulating NGF production in
cultured SCs, but little has been achieved. In the present
in vitro study, electrical stimulation (ES) was attempted to
stimulate cultured SCs to release NGF. Our data showed
that ES was capable of enhancing NGF release from cultured
SCs. An electrical field (1 Hz, 5 V/cm) caused a
4.1-fold increase in NGF releasefrom cultured SCs. The
ES-induced NGF release is calcium dependent. Depletion
of extracellular or/and intracellular calcium partially/
completely abolished the ES-induced NGF release. Further
pharmacological interventions showed that ES induces calcium
influx through T-type voltage-gated calcium channels
and mobilizes calcium from 1, 4, 5-trisphosphate-sensitive
stores andcaffeine/ryanodine-sensitive stores, both of which
contributed to the enhanced NGF release induced by ES. In
addition, a calcium-triggered exocytosis mechanism was
involved in the ES-induced NGF release from cultured
SCs. These findings show the feasibility of using ES in
stimulating SCs to release NGF, which holds great potential
in promoting nerve regeneration by enhancing
survival and outgrowth of damagednerves, and is of great
significance in nerve injury repair and neuronal tissue
engineering. VVC 2009 Wiley-Liss, Inc.
INTRODUCTION
Functional recovery is generally poor after nerve
injuries in which nerves must regenerate through long
distances to reinnervate their denervated targets. In
such cases, axotomized neurons require an extended
period of time to reach their targets, and Schwanncells
(SCs) in the distal stump may remain denervated for a
long time (Fu and Gordon, 1995a,b; Gordon et al., 2003).
The expression of neurotrophic factors progressively
declines with time in both axotomized motoneurons
and denervated SCs in the distal stumps after nerve
injuries (Boyd and Gordon, 2003; H€oke et al., 2002; Li
et al., 1997). As the expression of neurotrophic factors
declineswith time, there is a corresponding decline in
the capacities of axotomized neurons to regenerate and
of denervated SCs to support regenerating neurons and
their axons. The prolonged axotomy and chronic denervation
of SCs in the distal nerve stump significantly
limit the functional recovery after nerve injuries that
require axonal regeneration over a long distance
(Fu and Gordon, 1995a,b;Gordon et al., 2003). Therefore,
upregulating the expression of neurotrophic factors
in axotomized neurons and denervated SCs is important
in promoting functional recovery after nerve injuries.
Electrical stimulation (ES, 20 Hz) of the proximal
nerve stump promotes an earlier and striking upregulation
of brain-derived neurotrophic factor (BDNF) and its
receptor in the axotomized motoneuronsand sensory
neurons. This accelerated neurotrophic factor upregulation
correlates with striking accelerated axon outgrowth
across the surgical site after ES (Al-Majed et al., 2000a,
2004; Brushart et al., 2002, 2005; Geremia et al., 2007).
These findings indicate a critical role of endogenous
neurotrophic factors in axonal regeneration in the
peripheral nervous system. However, these...
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