Degeneration and regeneration of the nervous system

T1, T2, and magnetization transfer (MT) measurements were performed in vitro at 3 T and 37 degrees C on a variety of tissues: mouse liver, muscle, and heart; rat spinal cord and kidney; bovine optic nerve, cartilage, and white and gray matter; and human blood. The MR parameters were compared to those at 1.5 T. As expected, the T2 relaxation time constants and quantitative MT parameters (MT exchange rate, R, macromolecular pool fraction, M0B, and macromolecular T2 relaxation time, T2B) at 3 T were similar to those at 1.5 T. The T1 relaxation time values, however, for all measured tissues increased significantly with field strength. Consequently, the phenomenological MT parameter, magnetization transfer ratio, MTR, was lower by approximately 2 to 10%. Collectively, these results provide a useful reference for optimization of pulse sequence parameters for MRI at 3 T.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mrm.20605

T1, T2 relaxation and magnetization transfer in tissue at 3T

Collagen is the most widely distributed class of proteins in the human body. The use of collagen-based biomaterials in the field of tissue engineering applications has been intensively growing over the past decades. Multiple cross-linking methods were investigated and different combinations with other biopolymers were explored in order to improve tissue function. Collagen possesses a major advantage in being biodegradable, biocompatible, easily available and highly versatile. However, since collagen is a protein, it remains difficult to sterilize without alterations to its structure. This review presents a comprehensive overview of the various applications of collagen-based biomaterials developed for tissue engineering, aimed at providing a functional material for use in regenerative medicine from the laboratory bench to the patient bedside.

/pdf/collagen-based-biomaterials-for-tissue-engineering-37yrr8an7e.pdf

Collagen-Based Biomaterials for Tissue Engineering Applications

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

/pdf/neurotransmitter-triggered-transfer-of-exosomes-mediates-31u0thnxzw.pdf

Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.

https://science.sciencemag.org/content/sci/334/6063/1727.full.pdf

The Hedgehog Pathway Promotes Blood-Brain Barrier Integrity and CNS Immune Quiescence

Background: The purpose of this study was to determine the prevalence, cause, severity, and patterns of associated injuries of limb peripheral nerve injuries sustained by patients with multiple injuries seen at a regional Level 1 trauma center. Methods: Patients sustaining injuries to the radial, median, ulnar, sciatic, femoral, peroneal, or tibial nerves were identified using a prospectively collected computerized database, maintained by Sunnybrook Health Science Centre, and a detailed chart review was undertaken. Results: From a trauma population of 5,777 patients treated between January 1, 1986, and November 30, 1996, 162 patients were identified as having an injury to at least one of the peripheral nerves of interest, yielding a prevalence of 2.8%. These 162 patients sustained a total of 200 peripheral nerve injuries, 121 of which were in the upper extremity. The mean patient age was 34.6 years (SEM ± 1.1 year), and 83% of patients were male. The mean injury severity score was 23.1 (±0.90), and the mean length of hospital stay was 28 days (±1.8). Conclusions: Motor vehicles crashes predominated (46%) as the cause of injury. The most frequently injured nerve was the radial nerve (58 injuries), and in the lower limb, the peroneal nerve was most commonly injured (39 injuries). Diagnosis of a peripheral nerve injury was made within 4 days of admission to Sunnybrook Health Science Centre in 78% of the cases. Surgery was required to treat 54% of patients. Head injuries were the most common associated injury, occurring in 60% of patients. Other common associated injuries included fractures and dislocations. The present report aims to aid in identification and treatment of peripheral nerve injuries.

Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries.

Purpose: As alternatives to nerve grafts for peripheral nerve repair, we have synthesized 12 mm long poly(2- hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) porous tubes and studied their regenerative capacity for the repair of surgically-created 10 mm rat sciatic nerve gaps. We compared the in vivo regenerative efficacy of these artificial tubes with the gold standard, the nerve autograft. Methods: Tubes were assessed in vivo for their ability to support nerve regeneration at 4, 8, and 16 weeks post-implantation by histology, electrophysiology, histomorphometry, and reinnervated lateral gastrocnemius (LG) dry muscle mass. Results: Axonal regeneration within the tubes was observed by 8 weeks, with outcome parameters comparable to autografts. This finding was further supported by the electrophysiological and histomorphometric results. The 16 week tube group had a bimodal response, with 60% of the tubes having a similar response to autografts and the other 40% having significantly lower ( p< 0.05) outcome measures in several parameters. Conclusions: Axonal regeneration in artificial tubes was similar to that in autografts at 8 and 16 weeks, however, a bimodal distribution of regeneration was observed in 16 week tubes.

Peripheral nerve regeneration through a synthetic hydrogel nerve tube

In this review the authors intend to demonstrate the need for supplementing conventional repair of the injured nerve with alternative therapies, namely transplantation of stem or progenitor cells Although peripheral nerves do exhibit the potential to regenerate axons and reinnervate the end organ, outcome following severe nerve injury, even after repair, remains relatively poor This is likely because of the extensive injury zone that prevents axon outgrowth Even if outgrowth does occur, a relatively slow growth rate of regeneration results in prolonged denervation of the distal nerve Whereas denervated Schwann cells (SCs) are key players in the early regenerative success of peripheral nerves, protracted loss of axonal contact renders Schwann cells unreceptive for axonal regeneration Given that denervated Schwann cells appear to become effete, one logical approach is to support the distal denervated nerve environment by replacing host cells with those derived exogenously A number of different sources of stem/precursor cells are being explored for their potential application in the scenario of peripheral nerve injury The most promising candidate, transplant cells are derived from easily accessible sources such as the skin, bone marrow, or adipose tissue, all of which have demonstrated the capacity to differentiate into Schwann cell-like cells Although recent studies have shown that stem cells can act as promising and beneficial adjuncts to nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting The authors investigate the relevance of the delivery method (both the number and differentiation state of cells) on experimental outcomes, and seek to clarify whether stem cells must survive and differentiate in the injured nerve to convey a therapeutic effect As our laboratory uses skin-derived precursor cells (SKPCs) in various nerve injury paradigms, we relate our findings on cell fate to other published studies to demonstrate the need to quantify stem cell survival and differentiation for future studies

https://thejns.org/downloadpdf/journals/neurosurg-focus/26/2/article-pE2.pdf

Rajiv Midha

Papers

Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries.

Peripheral nerve regeneration through a synthetic hydrogel nerve tube

Practical considerations concerning the use of stem cells for peripheral nerve repair.

Macrophages Regulate Schwann Cell Maturation after Nerve Injury.

Supplementation of acellular nerve grafts with skin derived precursor cells promotes peripheral nerve regeneration