Abstract
The acceleration of peripheral nerve regeneration is crucial for functional nerve recovery. Our previous study demonstrated that human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSC) promote sciatic nerve recovery and regeneration via the direct upregulation and release of neurotrophic factors. However, the immunomodulatory role of hWJ-MSC in sciatic nerve recovery remains unclear. The effects of hWJ-MSC on innate immunity, represented by macrophages, natural killer cells, and dendritic cells, as well as on adaptive immunity, represented by CD4+ T, CD8+ T, B, and regulatory T cells (Tregs), were examined using flow cytometry. Interestingly, a significantly increased level of Tregs was detected in blood, lymph nodes (LNs), and nerve-infiltrating cells on POD7, 15, 21, and 35. Anti-inflammatory cytokines, such as IL-4 and IL-10, were significantly upregulated in the LNs and nerves of hWJ-MSC-treated mice. Treg depletion neutralized the improved effects of hWJ-MSC on sciatic nerve recovery. In contrast, Treg administration promoted the functional recovery of five-toe spread and gait stance. hWJ-MSC also expressed high levels of the anti-inflammatory cytokines TGF-β and IL-35. This study indicated that hWJ-MSC induce Treg development to modulate the balance between pro- and anti-inflammation at the injured sciatic nerve by secreting higher levels of anti-inflammatory cytokines.
Highlights
Peripheral nerve injuries differ from central nervous system (CNS) injuries [1], which usually affect end-target organs, potentially causing denervation and loss of function
Our previous study demonstrated that the topical application of human Wharton’s jelly-derived mesenchymal stem cells (hWJ-mesenchymal stem cells (MSC)) accelerates signs of sciatic nerve recovery, such as five-toe spread and toe-off phase, partly via the direct upregulation and release of neurotrophic factors (Supplementary Figure S1A,B) [10]
Macrophages and dendritic cells (DCs) were detected at a similar level in lymphoid organs and nerve-infiltrating cells between the buffer and hWJ-MSC groups at four time points
Summary
Peripheral nerve injuries differ from central nervous system (CNS) injuries [1], which usually affect end-target organs, potentially causing denervation and loss of function. The recovery of movement and sensation are highly time-sensitive processes and the loss of reinnervation [2] can result in the permanent loss of function of a limb, compounding disability, and a decrease in quality of life. Injuries located farther away from their end-target organs or muscles take a much longer time to regenerate, which causes the atrophy of motor end plates, eventually resulting in muscle atrophy [3]. Inflammatory responses play an important role during Wallerian degeneration and axonal growth [4,5,6]. The coordination of pro- and anti-inflammatory signals during Wallerian degeneration is crucial and must be tightly controlled to ensure successful axon regeneration
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