Effect of modulating macrophage phenotype on peripheral nerve repair

Mokarram, Nassir; Merchant, Alishah; Mukhatyar, Vivek; Patel, Gaurangkumar; Bellamkonda, Ravi V.

doi:10.1016/j.biomaterials.2012.08.050

Cited by 290 publications

(257 citation statements)

References 60 publications

(101 reference statements)

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“…Pro‐inflammatory populations of macrophages significantly suppress peripheral nerve repair (Mokarram et al, 2012), pertinent to our suggestion that the hyperinflammatory environment is a major inhibitory factor of nerve recovery in old mice. Acetylsalicylic acid (ASA), shown to decrease the macrophage number in sciatic nerves (Schulz et al, 2016), was the drug chosen to assess an anti‐inflammatory therapy for old mice subjected to peripheral nerve injury—reasoning that repressing injury‐induced abnormal hyperinflammatory responses should augment nerve recovery in old mice.…”

Section: Discussionsupporting

confidence: 60%

“…Hallmarks of Wallerian degeneration are as follows: (a) detachment of resident Schwann cells from associated axons, (b) transition of these Schwann cells into a “repair Schwann cell” phenotype, (c) breakdown of the blood–nerve barrier, and (d) influx of macrophages into the tissue that, (e) in concert with “repair Schwann cells,” phagocytize axonal and myelin‐derived debris (Chen, Yu, & Strickland, 2007; Jessen, Mirsky, & Lloyd, 2015). During the regeneration phase, macrophages support “repair Schwann cells” in mediating axonal regrowth to re‐innervate the target tissue (Cattin et al, 2015; Mietto, Mostacada, & Martinez, 2015; Mokarram, Merchant, Mukhatyar, Patel, & Bellamkonda, 2012). Regeneration is completed when inflammatory processes resolve and “repair Schwann cells” redifferentiate.…”

Section: Introductionmentioning

confidence: 99%

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Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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“…They implanted polysulfone nerve-bridging tubes filled with 0.7% agarose hydrogel mixed with either IFNg to promote the M1 phenotype or IL4 for M2a, or an unloaded control. 68 This drug delivery platform demonstrated release via diffusion over 24 h for both IFNg and IL4 in vitro.…”

Section: Delivery Of Cytokines To Modulate Phenotype Of Endogenous Mamentioning

confidence: 99%

Drug delivery strategies to control macrophages for tissue repair and regeneration

Garash

Bajpai

Marcinkiewicz

et al. 2016

Exp Biol Med (Maywood)

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Tissue repair and regeneration is a complex process. Our bodies have an excellent capacity to regenerate damaged tissues in many situations. However, tissue healing is impaired in injuries that exceed a critical size or are exacerbated by chronic inflammatory diseases like diabetes. In these instances, biomaterials and drug delivery strategies are often required to facilitate tissue regeneration by providing physical and biochemical cues. Inflammation is the body's response to injury. It is critical for wound healing and biomaterial integration and vascularization, as long as the timing is well controlled. For example, chronic inflammation is well known to impair healing in chronic wounds. In this review, we highlight the importance of a well-controlled inflammatory response, primarily mediated by macrophages in tissue repair and regeneration and discuss various strategies designed to promote regeneration by controlling macrophage behavior. These strategies include temporally controlled delivery of anti-inflammatory drugs, delivery of macrophages as cellular therapy, controlled release of cytokines that modulate macrophage phenotype, and the design of nanoparticles that exploit the inherent phagocytic behavior of macrophages. A clear outcome of this review is that a deeper understanding of the role and timing of complex macrophage phenotypes or activation states is required to fully harness their abilities with drug delivery strategies.

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“…In addition to electrical stimulation of the central nerve stump of a transected peripheral nerve, the use of electrically conductive biodegradable hydrogel consisting of oligo (polyethylene glycol) fumarate (OPF) and polypyrrole (PPy) increases neurite outgrowth [319], and when containing single-walled carbon nanotubes (SWCNT) support the viability of Schwann cells within the nerve gap [303]. Thus, an electrically-conductive SWCNT collagen I-Matrigel biomaterial may be suitable for neural tissue engineering and by sustaining populations of Schwann cells [303].…”

Section: Electrical Stimulationmentioning

confidence: 99%

Promoting Axon Regeneration and Neurological Recovery Following Traumatic Peripheral Nerve Injuries

Kuffler¹

2015

Int J Neurorehabilitation Eng

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Repairing Peripheral Nerves following Traumas Nerve crushWithin several days of crushing a peripheral nerve, the injured axons begin to regenerate through their distal pathway until they reach their original targets with which they restore neurological function. The larger the number of axons that regenerate through the distal nerve, the greater the extent of neurological recovery [1][2][3]. The number of axons that regenerate, and thus neurological recovery, is influenced by the physiological state of the distal denervated nerve pathway [4][5][6][7].Following a peripheral nerve crush, the injured axons begin to regenerate within 2 days of injury [8]. They may regenerate to their targets through their original pathway in association with and promoted by its Schwann cells, the neurotrophic factors they release, and the Schwann cell extracellular matrix [1,4,[9][10][11][12][13][14]. Thus, the distal nerve provides a simple means for promoting and directing the regenerating axons to their original targets [15][16][17][18]. However, when a nerve has a gap, the gap must be bridged with a material that is permissive to and promotes axon regeneration across the entire gap to reach the distal nerve stump, through which the axons must then be able to regenerate.The Schwann cells in the denervated distal nerve release neurotrophic factors that promote axon regeneration, but also release extracellular matrix components that promote and inhibit axon regeneration [19][20][21][22][23][24][25][26]. Thus, regeneration through the distal nerve is a balance of the influences of factors that both promote and inhibit regeneration. If the Schwann cells are present, such as after a simple nerve crush, virtually 100% of the axons regenerate and they innervate all the denervated synaptic sites. If the Schwann cells within the distal nerve pathway are killed, leaving only the extracellular matrix intact, the number of axons that regenerates to their targets decreases by 94%. This is because the factors required to trigger the regenerating axons to branch at extracellular matrix branch points are missing, axons do not branch, and therefore each axon reinnervates only a single denervated muscle fiber. Thus, Schwann cells along the distal nerve pathway and a AbstractFollowing a peripheral nerve crush, or when a peripheral the nerve is transected and the nerve stumps anastomosed, neurological recovery is generally excellent. This is because the axons merely have to regenerate through the distal portion of the nerve through the existing extracellular matrix of the denervated Schwann cells that direct and promote them to their distant denervated motor and sensory targets. However, when a length of a peripheral nerve is destroyed, and anastomosis is not possible, the standard surgical repair technique is to graft a length/s of autologous sensory nerve into the gap. Neurological recovery is generally good if the nerve gap is <2 cm in length, the repair is performed <4 months post trauma, and the patients are <25 years of age. Because the nerve ...

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Effect of modulating macrophage phenotype on peripheral nerve repair

Cited by 290 publications

References 60 publications

Inflammaging impairs peripheral nerve maintenance and regeneration

Inflammaging impairs peripheral nerve maintenance and regeneration

Drug delivery strategies to control macrophages for tissue repair and regeneration

Promoting Axon Regeneration and Neurological Recovery Following Traumatic Peripheral Nerve Injuries

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