Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension

Saffari, Sara; Saffari, Tiam M.; Chan, K. Ming; Borschel, Gregory H.; Shin, Alexander Y.

doi:10.1002/bit.27916

Cited by 8 publications

(10 citation statements)

References 67 publications

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“…Lifelong immunosuppressant use is not required as in other transplantations; its use until regeneration is completed is sufficient 11,12 . Saffari et al 13 found that MSCs or tacrolimus treatment alone improved neural outgrowth and, when used in combination, offered superior results in both autografts and allografts. Although tacrolimus has been shown to have positive effects on autologous and cellularized allograft nerve regeneration, better results were not obtained in the cellularized group with tacrolimus compared with the decellularized group in this study 14 …”

Section: Discussionmentioning

confidence: 99%

The Effects of Adipose-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cell–Originating Exosomes on Nerve Allograft Regeneration

Koplay¹,

Yıldıran²,

Dursunoğlu

et al. 2023

Ann Plast Surg

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Introduction Nerve regeneration has been the subject of many studies because of its complex mechanism and functional outcome. Mesenchymal stem cells and exosomes are promising factors in regeneration in many areas. Reconstruction of nerve defects is a controversial issue, and nerve allografts are promising alternatives with many advantages. In this study, it is aimed to evaluate the nerve regeneration in cellularized and decellularized nerve allografts and whether it is possible to accelerate this process with adipose-derived mesenchymal stem cells (ad MSC) or ad MSC–originating exosomes. Method This study was performed with 36 Lewis and 18 Brown Norway isogenic male rats aged 10 to 12 weeks and weighing 300 to 350 g. The Lewis rats were divided into 6 groups. Nerve allografts at a length of 12 mm that were obtained from the Brown Norway rats' proximal portion of both sciatic nerve branching points were coapted as cellularized in group A and decellularized in group B to the sciatic nerve defects of the Lewis rats. Group A received oral tacrolimus (0.2 mg/kg) for 30 days. Perineural saline (A1-B1), ad MSC (A2-B2), or ad MSC–originating exosomes (A3-B3) were applied to these groups. Walking track analysis, pinch-prick test and electromyelography were applied at the 8th and 16th weeks following surgery. Nerves were examined histopathologically at the 16th week. Results Between cellularized groups, better results were shown in A3 about axon-myelin regeneration/organization (P = 0.001), endoneural connective tissue (P = 0.005), and inflammation (P = 0.004). Better results were shown in the B2 and B3 groups electromyelographicaly about latency period (P = 0.033) and action potential (P = 0.008) at late period, and histomorphologicaly at vascularization (P = 0.012). Discussion It is argued that regeneration is accelerated with decellularization of nerve allografts by removing the chondroidin sulfate proteoglycans. The positive effects of stem cells are derived by exosomes without the cell-related disadvantages. In this study, better results were obtained by decellularization and perineural application of ad MSC and/or ad MSC exosome.

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Section: Discussionmentioning

confidence: 99%

The Effects of Adipose-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cell–Originating Exosomes on Nerve Allograft Regeneration

Koplay¹,

Yıldıran²,

Dursunoğlu

et al. 2023

Ann Plast Surg

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“…Each group consisted of nine samples, and at least six samples per group were included to ensure sufficient statistical power based on prior studies (Saffari, Saffari, Chan, et al, 2021;Tajdaran et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…PEP, an off-the-shelf exosome product, has the potential to overcome these limitations as it is readily available, easily accessible, less immunogenic, less time invasive, and with minimal risks of cell contamination (Dong et al, 2019;Liu et al, 2020;Qing et al, 2018) as well as human-derived PEP, resulted in enhanced neuroregenerative effects (Bucan et al, 2019;Dong et al, 2019;Ikumi et al, 2021;Wang et al, 2023). Second, this in vitro model lacks the 3D, chemical and mechanical cues of nerve regeneration and an in vivo model (Clements et al, 2017;Saffari, Saffari, Chan, et al, 2021), and lacks the evaluation of the effect of PEP on nerve regeneration over time.…”

Section: Discussionmentioning

confidence: 99%

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Dose–response analysis after administration of a human platelet‐derived exosome product on neurite outgrowth in vitro

Saffari

Rademakers

Pulos

et al. 2023

Biotech & Bioengineering

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Modulating the nerve's local microenvironment using exosomes is proposed to enhance nerve regeneration. This study aimed to determine the optimal dose of purified exosome product (PEP) required to exert maximal neurite extension. An in vitro dorsal root ganglion (DRG) neurite outgrowth assay was used to evaluate the effect of treatment with (i) 5% PEP, (ii) 10% PEP, (iii) 15% PEP, or (iv) 20% PEP on neurite extension (N = 9/group), compared to untreated controls. After 72 h, neurite extension was measured to quantify nerve regeneration. Live cell imaging was used to visualize neurite outgrowth during incubation. Treatment with 5% PEP resulted in the longest neurite extension and was superior to the untreated DRG (p = 0.003). Treatment with 10% PEP, 15% PEP, and 20% PEP was found to be comparable to controls (p = 0.12, p = 0.06, and p = 0.41, respectively) and each other. Live cell imaging suggested that PEP migrated towards the DRG neural regeneration site, compared to the persistent homogenous distribution of PEP in culture media alone. 5% PEP was found to be the optimal concentration for nerve regeneration based on this in vitro dose–response analysis.

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“…The in vivo myelination capacity was also unexplored. A previous study also combined the application of mesenchymal stem cells and local tacrolimus delivery to promote nerve regeneration ( Saffari et al, 2021 ). However, this research centered on the anti-inflammatory effect rather than the neurotrophic action of tacrolimus in cell and nerve graft transplantation.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus-Induced Neurotrophic Differentiation of Adipose-Derived Stem Cells as Novel Therapeutic Method for Peripheral Nerve Injury

Yao

Yan²,

Li³

et al. 2021

Front. Cell. Neurosci.

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Peripheral nerve injuries (PNIs) are frequent traumatic injuries across the globe. Severe PNIs result in irreversible loss of axons and myelin sheaths and disability of motor and sensory function. Schwann cells can secrete neurotrophic factors and myelinate the injured axons to repair PNIs. However, Schwann cells are hard to harvest and expand in vitro, which limit their clinical use. Adipose-derived stem cells (ADSCs) are easily accessible and have the potential to acquire neurotrophic phenotype under the induction of an established protocol. It has been noticed that Tacrolimus/FK506 promotes peripheral nerve regeneration, despite the mechanism of its pro-neurogenic capacity remains undefined. Herein, we investigated the neurotrophic capacity of ADSCs under the stimulation of tacrolimus. ADSCs were cultured in the induction medium for 18 days to differentiate along the glial lineage and were subjected to FK506 stimulation for the last 3 days. We discovered that FK506 greatly enhanced the neurotrophic phenotype of ADSCs which potentiated the nerve regeneration in a crush injury model. This work explored the novel application of FK506 synergized with ADSCs and thus shed promising light on the treatment of severe PNIs.

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Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension

Abstract: Background: The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts.

Cited by 8 publications

References 67 publications

The Effects of Adipose-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cell–Originating Exosomes on Nerve Allograft Regeneration

The Effects of Adipose-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cell–Originating Exosomes on Nerve Allograft Regeneration

Dose–response analysis after administration of a human platelet‐derived exosome product on neurite outgrowth in vitro

Tacrolimus-Induced Neurotrophic Differentiation of Adipose-Derived Stem Cells as Novel Therapeutic Method for Peripheral Nerve Injury

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