Targeting Matrix Metalloproteinases: A Potential Strategy for Improving Cell Transplantation for Nervous System Repair

Cell transplantation shows promise for repair of the injured nervous system, including spinal cord injury (SCI) and peripheral nerve injury (PNI). There are, however, still problems hampering these therapies moving from bench to bedside, and the methods need optimization. Three-dimensional (3D) cell culture systems are suggested to improve outcomes, bridging the gap between the in vitro and in vivo environments. In such constructs, cells are allowed to interact with each other and with the extracellular matrix (ECM) in 3D as they do in vivo. Transplanting cells in 3D constructs, rather than in suspension, is thought to promote cell survival and maintain important cellular behaviors. One such critical behavior is cell migration into and within the injury site. Understanding and controlling the migratory capability of 3D-cultured cells is therefore pivotal for developing better transplantation techniques. ECM remodelling can influence numerous cellular functions, including cell migration and matrix metalloproteinases (MMPs) are important enzymes for ECM modulation. Here, we discuss the idea of modulating MMPs to control cell migration in 3D culture systems, which can improve the therapeutic potential of cells transplanted in 3D.

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Oligodendrocyte precursor (O-2A progenitor cell) migration; a model system for the study of cell migration in the developing central nervous system

Development ◽

10.1242/dev.119.supplement.219 ◽

1993 ◽

Vol 119 (Supplement) ◽

pp. 219-225 ◽

Cited By ~ 2

Author(s):

B. W. Kiernan ◽

Charles ffrench-Constant

Keyword(s):

Nervous System ◽

Cell Migration ◽

Progenitor Cell ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Large Numbers ◽

Multicellular Organisms ◽

Developing Nervous System

Cell migration plays an important role in the development of complex multicellular organisms. The molecular mechanisms that regulate this migration arc therefore of great interest. Unfortunately, however, analysis of cell migration in vertebrates is hampered by the inaccessability of the cells and the difficulty of manipulating their environment within the embryo. This review focusses on one particular migratory cell population, the oligodendrocyte p1ecursor cell or O-2A progenitor cell, that gives rise to the myelin-forming oligodendrocytes within the CNS. These cells mi grate extensively during normal development. They can be purified and grown in large numbers in cell culture, so allowing the use of reductionist approaches using cell and molecular biology techniques. Moreover, cultured cells will migrate within the CNS following transplantation. As a result, the migration of these cells in vivo can be analysed following manipulation in vitro. Taken together, we believe that the different properties of these cells makes them excellent candidates for studies addressing the control of cell migration in the developing nervous system.

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Monitoring stem cell migration in the nervous system by in vivo magnetic resonance imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0693 ◽

2005 ◽

Vol 25 (1_suppl) ◽

pp. S692-S692

Author(s):

Mathias Hoehn ◽

Uwe Himmelreich ◽

Ralph Weber ◽

Pedro Ramos-Cabrer ◽

Susanne Wegener ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Nervous System ◽

Stem Cell ◽

Cell Migration ◽

Magnetic Resonance ◽

Resonance Imaging ◽

Stem Cell Migration

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Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-210 ◽

1982 ◽

Vol 60 (11) ◽

pp. 1415-1424 ◽

Cited By ~ 150

Author(s):

H. B. Demopoulos ◽

E. S. Flamm ◽

M. L. Seligman ◽

D. D. Pietronigro ◽

J. Tomasula ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Free Radical ◽

Tissue Injury ◽

Functional Restoration ◽

Radical Reactions ◽

Free Radical Reactions ◽

Cord Injury

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.

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Nitrous Oxide Impairs Axon Regeneration after Nervous System Injury in Male Rats

Anesthesiology ◽

10.1097/aln.0000000000002906 ◽

2019 ◽

Vol 131 (5) ◽

pp. 1063-1076

Author(s):

Krista J. Stewart ◽

Bermans J. Iskandar ◽

Brenton M. Meier ◽

Elias B. Rizk ◽

Nithya Hariharan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Nervous System ◽

Nitrous Oxide ◽

Folic Acid ◽

Functional Recovery ◽

Axon Regeneration ◽

Retinal Ganglion ◽

Cord Injury

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Nitrous oxide can induce neurotoxicity. The authors hypothesized that exposure to nitrous oxide impairs axonal regeneration and functional recovery after central nervous system injury. Methods The consequences of single and serial in vivo nitrous oxide exposures on axon regeneration in four experimental male rat models of nervous system injury were measured: in vitro axon regeneration in cell culture after in vivo nitrous oxide administration, in vivo axon regeneration after sharp spinal cord injury, in vivo axon regeneration after sharp optic nerve injury, and in vivo functional recovery after blunt contusion spinal cord injury. Results In vitro axon regeneration 48 h after a single in vivo 70% N2O exposure is less than half that in the absence of nitrous oxide (mean ± SD, 478 ± 275 um; n = 48) versus 210 ± 152 um (n = 48; P < 0.0001). A single exposure to 80% N2O inhibits the beneficial effects of folic acid on in vivo axonal regeneration after sharp spinal cord injury (13.4 ± 7.1% regenerating neurons [n = 12] vs. 0.6 ± 0.7% regenerating neurons [n = 4], P = 0.004). Serial 80% N2O administration reverses the benefit of folic acid on in vivo retinal ganglion cell axon regeneration after sharp optic nerve injury (1277 ± 180 regenerating retinal ganglion cells [n = 7] vs. 895 ± 164 regenerating retinal ganglion cells [n = 7], P = 0.005). Serial 80% N2O exposures reverses the benefit of folic acid on in vivo functional recovery after blunt spinal cord contusion (estimate for fixed effects ± standard error of the estimate: folic acid 5.60 ± 0.54 [n = 9] vs. folic acid + 80% N2O 5.19 ± 0.62 [n = 7], P < 0.0001). Conclusions These data indicate that nitrous oxide can impair the ability of central nervous system neurons to regenerate axons after sharp and blunt trauma.

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Zinc Regulates Glucose Metabolism of the Spinal Cord and Neurons and Promotes Functional Recovery after Spinal Cord Injury through the AMPK Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4331625 ◽

2021 ◽

Vol 2021 ◽

pp. 1-27

Author(s):

Hengshuo Hu ◽

Nan Xia ◽

Jiaquan Lin ◽

Daoyong Li ◽

Chuanjie Zhang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Nervous System ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Functional Recovery ◽

Glucose Metabolism Disorders ◽

Cord Injury

Spinal cord injury (SCI) is a traumatic disease that can cause severe nervous system dysfunction. SCI often causes spinal cord mitochondrial dysfunction and produces glucose metabolism disorders, which affect neuronal survival. Zinc is an essential trace element in the human body and plays multiple roles in the nervous system. This experiment is intended to evaluate whether zinc can regulate the spinal cord and neuronal glucose metabolism and promote motor functional recovery after SCI. Then we explore its molecular mechanism. We evaluated the function of zinc from the aspects of glucose uptake and the protection of the mitochondria in vivo and in vitro. The results showed that zinc elevated the expression level of GLUT4 and promoted glucose uptake. Zinc enhanced the expression of proteins such as PGC-1α and NRF2, reduced oxidative stress, and promoted mitochondrial production. In addition, zinc decreased neuronal apoptosis and promoted the recovery of motor function in SCI mice. After administration of AMPK inhibitor, the therapeutic effect of zinc was reversed. Therefore, we concluded that zinc regulated the glucose metabolism of the spinal cord and neurons and promoted functional recovery after SCI through the AMPK pathway, which is expected to become a potential treatment strategy for SCI.

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Novel C1q receptor-mediated signaling controls neural stem cell behavior and neurorepair

eLife ◽

10.7554/elife.55732 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Francisca Benavente ◽

Katja M Piltti ◽

Mitra J Hooshmand ◽

Aileen A Nava ◽

Anita Lakatos ◽

...

Keyword(s):

Intracellular Signaling ◽

Control Cell ◽

Screening Strategy ◽

Receptor Expression ◽

Therapeutic Window ◽

Cell Behavior ◽

Human Neural Stem Cells ◽

Cord Injury

C1q plays a key role as a recognition molecule in the immune system, driving autocatalytic complement cascade activation and acting as an opsonin. We have previously reported a non-immune role of complement C1q modulating the migration and fate of human neural stem cells (hNSC); however, the mechanism underlying these effects has not yet been identified. Here, we show for the first time that C1q acts as a functional hNSC ligand, inducing intracellular signaling to control cell behavior. Using an unbiased screening strategy, we identified five transmembrane C1q signaling/receptor candidates in hNSC (CD44, GPR62, BAI1, c-MET, and ADCY5). We further investigated the interaction between C1q and CD44 , demonstrating that CD44 mediates C1q induced hNSC signaling and chemotaxis in vitro, and hNSC migration and functional repair in vivo after spinal cord injury. These results reveal a receptor-mediated mechanism for C1q modulation of NSC behavior and show that modification of C1q receptor expression can expand the therapeutic window for hNSC transplantation.

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Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions

10.1101/2020.04.30.068965 ◽

2020 ◽

Author(s):

David O. Dias ◽

Jannis Kalkitsas ◽

Yildiz Kelahmetoglu ◽

Cynthia P. Estrada ◽

Jemal Tatarishvili ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Mouse Models ◽

Stromal Cells ◽

Primary Source ◽

Lineage Tracing ◽

Fibrotic Tissue ◽

Cord Injury

AbstractFibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models developing fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes.We uncover pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.

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To Better Generate Organoids, What Can We Learn From Teratomas?

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.700482 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hongyu Li ◽

Lixiong Gao ◽

Jinlin Du ◽

Tianju Ma ◽

Zi Ye ◽

...

Keyword(s):

Animal Models ◽

Disease Modeling ◽

3D Culture ◽

Cellular Heterogeneity ◽

Developmental Studies ◽

Genomic Profile ◽

Organization Studies ◽

Culture Systems

The genomic profile of animal models is not completely matched with the genomic profile of humans, and 2D cultures do not represent the cellular heterogeneity and tissue architecture found in tissues of their origin. Derived from 3D culture systems, organoids establish a crucial bridge between 2D cell cultures and in vivo animal models. Organoids have wide and promising applications in developmental research, disease modeling, drug screening, precision therapy, and regenerative medicine. However, current organoids represent only single or partial components of a tissue, which lack blood vessels, native microenvironment, communication with near tissues, and a continuous dorsal-ventral axis within 3D culture systems. Although efforts have been made to solve these problems, unfortunately, there is no ideal method. Teratoma, which has been frequently studied in pathological conditions, was recently discovered as a new in vivo model for developmental studies. In contrast to organoids, teratomas have vascularized 3D structures and regions of complex tissue-like organization. Studies have demonstrated that teratomas can be used to mimic multilineage human development, enrich specific somatic progenitor/stem cells, and even generate brain organoids. These results provide unique opportunities to promote our understanding of the vascularization and maturation of organoids. In this review, we first summarize the basic characteristics, applications, and limitations of both organoids and teratomas and further discuss the possibility that in vivo teratoma systems can be used to promote the vascularization and maturation of organoids within an in vitro 3D culture system.

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