Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

Abstract

Introduction:The immuno-microenvironment of injured nerves adversely affects mesenchymal stem cell (MSC) therapy for neurotmesis. Magnetic resonance imaging (MRI) can be used noninvasively to monitor nerve degeneration and regeneration. The aim of this study was to investigate nerve repair after MSC transplantation combined with microenvironment immunomodulation in neurotmesis by using multiparametric MRI.Methods: Rats with sciatic nerve transection and surgical coaptation were treated with MSCs combined with immunomodulation or MSCs alone. Serial multiparametric MRI examinations were performed over an 8-week period after surgery.Results: Nerves treated with MSCs combined with immunomodulation showed better functional recovery, rapid recovery of nerve T2, fractional anisotropy and radial diffusivity values, and more rapid restoration of the fiber tracks than nerves treated with MSCs alone.Discussion: Transplantation of MSCs in combination with immunomodulation can exert a synergistic repair effect on neurotmesis, which can be monitored by multiparametric MRI. K E Y W O R D Simmunomodulation, magnetic resonance imaging, mesenchymal stem cells, peripheral nerve injuries, tacrolimus, toll-like receptors Abbreviations: AD, axial diffusivity; BDNF, brain-derived neurotrophic factor; DTI, diffusion tensor imaging; DTT, diffusion tensor tractography; ELISA, enzyme-linked immunosorbent assay; FA, fractional anisotropy; FKBP, FK-binding protein; GDNF, glial cell-derived neurotrophic factor; GFP, green fluorescent protein; LPS, lipopolysaccharide; MD, mean diffusivity; MRI, magnetic resonance imaging; MSC, mesenchymal stem cell; PBS, phosphate-buffered saline; RD, radial diffusivity; SD, Sprague-Dawley; SFI, sciatic nerve function index; SPRR1A, small proline-rich protein 1A; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α.Zehong Yang and Chushan Zheng contributed equally to this work.

Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension

“…Although the independent effect of MSCs and FK506 has been previously shown to enhance nerve regeneration (Doolabh & Mackinnon, 1999; Gold et al, 1994, 1995; Konofaos & Terzis, 2013; Sayad‐Fathi et al, 2019; Tajdaran et al, 2015; Tajdaran, Chan, Zhang, et al, 2019; Yang et al, 2020; Yousefi et al, 2019), the combined interaction and comparison of MSCs and local FK506 has not been extensively investigated. In this study, the effect of MSCs and FK506 was successfully investigated in an in vitro model to elucidate a synergistic effect of stem cells and local immunosuppression with respect to nerve regeneration.…”

“…No significant differences were found in neurite extension between sural and peroneal nerves within each experimental group (p > 0.05). Mackinnon, 1999;Gold et al, 1994Gold et al, , 1995Konofaos & Terzis, 2013;Sayad-Fathi et al, 2019;Tajdaran et al, 2015;Tajdaran, Chan, Zhang, et al, 2019;Yang et al, 2020;Yousefi et al, 2019), the combined interaction and comparison of MSCs and local FK506 has not been extensively investigated. In this study, the effect of MSCs and FK506…”

“…Adipose-derived MSCs are ideal for translation to clinical use as they are easily accessible and proliferate rapidly (di Summa et al, 2010;Saffari Saffari, Ulrich, et al, 2021;Yoshimura et al, 2007). The survivability and the effect of transplanted MSCs has been impeded by the unfavorable immune microenvironment by potential immunological reactions (Yang et al, 2020). Tacrolimus (FK506), an FDA approved immunosuppressant, is used for prevention of allograft rejection after solid organ transplantation and has become the cornerstone of modern immunosuppressive therapy (Brunet et al, 2019;Ekberg et al, 2007;Kasiske et al, 2010;Starzl et al, 1989;Zijlstra et al, 2015).…”

“…Providing biological support to decellularized allografts by adding host‐derived stem cells while modulating their environment with systemic or local immunosuppression may further improve decellularized allograft outcomes (Bain et al, 1988; Mackinnon et al, 2001). Adipose‐derived mesenchymal stem cell (MSC) transplantation has been widely studied in tissue engineering to enhance nerve regeneration in preclinical research (Sayad‐Fathi et al, 2019; Yang et al, 2020; Yousefi et al, 2019). MSCs can stimulate and support nerve regeneration by secreting growth factors, by differentiating into supporting cells, and by suppressing inflammatory reactions and oxidative stress (Hundepool et al, 2014; Kingham et al, 2014; Tomita et al, 2013).…”

“…Adipose‐derived MSCs are ideal for translation to clinical use as they are easily accessible and proliferate rapidly (di Summa et al, 2010; Saffari Saffari, Ulrich, et al, 2021; Yoshimura et al, 2007). The survivability and the effect of transplanted MSCs has been impeded by the unfavorable immune microenvironment by potential immunological reactions (Yang et al, 2020).…”