Diminished Schwann Cell Repair Responses Underlie Age-Associated Impaired Axonal Regeneration

Abstract

SUMMARY The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro nor in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired de-differentiation, myelin clearance and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.

Inflammaging impairs peripheral nerve maintenance and regeneration

“…Engaging several methods, we set out to comprehensively describe age‐dependent changes on functional, structural, cellular, and molecular levels. Our experimental design confirmed and further detailed previous work in this area (Figures 1 and 2) (He, Yadgarov, Sharif, & McCluskey, 2012; Painter et al, 2014; Scheib & Hoke, 2016; Verdu et al, 2000). …”

“…A growing body of work demonstrates age‐dependent decline of peripheral nerve regeneration capacity (Painter et al, 2014; Verdu et al, 2000; Wang et al, 2007), but insight into underlying mechanisms remains limited. To better understand age‐dependent factors impacting on peripheral nerve regeneration, we performed sciatic nerve crush injuries on C57BL/6 J mice of two different ages.…”

“…Two key studies have verified that the regenerating axonal environment is defective in old animals (Painter et al, 2014; Scheib & Hoke, 2016). The former observed age‐dependent differences in Schwann cell behavior and delayed repair program activation.…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…The outcome depends on the injury type: Complete nerve transection has a worse outcome than nerve crush due to mis-directed axon growth, and proximal injuries also have a poorer outcome than distal ones due to the slow (1 mm/day) rate of axon regrowth (Fu and Gordon, 1995). In addition, aged Schwann cells are less supportive of axon outgrowth than young Schwann cells and might produce less efficiently beneficial growth and metabolic factors (Painter et al, 2014). Traumatic nerve injury is followed by stereotypic events called Wallerian degeneration, i.e.…”

Focal release of neurotrophic factors by biodegradable microspheres enhance motor and sensory axonal regeneration in vitro and in vivo

“…The use of nerve conduits to bridge short or mid length gaps is a good alternative to autografts (Arslantunali et al, 2014), although regeneration is slowed during the initial phase compared to autograft (Boeckstyns et al, 2013). Several parameters affect the rate of axonal regeneration, including the distance between stumps (Scherman et al, 2001), the age of the subject (Kang et al, 2013;Painter et al, 2014;Verdú et al, 2008), the time after repair and the distance between the lesion site and end organ (Gordon et al, 2003). Indeed, the time from injury to target reinnervation is the most important predictor of the degree of functional recovery (Krarup et al, 2002), emphasizing that factors that control early axonal outgrowth influence the final level of recovery attained even years later.…”