Inflammatory Pathways in Spinal Cord Injury

David, Samuel; Zarruk, Juan G.; Ghasemlou, Nader

doi:10.1016/b978-0-12-407178-0.00006-5

Cited by 81 publications

(58 citation statements)

References 104 publications

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“…To simulate post-SCI inflammatory pathology (23) and evaluate the antiinflammatory potential of the scaffolded hMSCs, we challenged the organotypic DRG coculture system with LPS at 18 h after the assay initiation (20,24). Following a dose escalation of LPS (20 pg/mL to 1,000 ng/mL), a graded increase of TNF-α expression was triggered; above the LPS dose of 1,000 ng/mL, TNF-α production in the DRG plateaued (Fig.…”

Section: Evaluation Of Antiinflammatory Effects Of Scaffolded Hmscs Imentioning

confidence: 99%

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.spinal cord injury | recovery neurobiology | mesenchymal stromal stem cell | PLGA | locomotion R epair of neurotrauma, stroke, and neurodegenerative diseases remains an unmet medical demand because of their pathophysiological complexity and the limited spontaneous healing capacity of adult mammalian CNS. Human mesenchymal stromal stem cells (hMSCs) offer autologous transplantation feasibility (1-4) and have been studied both experimentally and clinically for traumatic brain injury (TBI) and spinal cord injury (SCI) (5-8). Although MSCs possess homeostatic and proneurogenic activities (7, 9), studies relying on neural transdifferentiation (i.e., putative differentiations of MSCs into neural cells without reentering the pluripotency phase) did not show long-term functional improvement in SCI models. The poor outcomes were attributed mainly to suboptimal survival of MSCs, leaving key therapeutic mechanisms undetermined (10). We previously established a 3D cell delivery technology by seeding neural stem cells (NSCs) in biodegradable polymer scaffolds that significantly improved donor efficacy and enabled investigation of NSC repair mechanisms in t...

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Section: Evaluation Of Antiinflammatory Effects Of Scaffolded Hmscs Imentioning

confidence: 99%

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Ropper

Thakor

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…barrier dysfunction [106]. H aider et al investigated the role of the apoptotic cell secretome in a rodent spinal cord injury model [104].…”

Section: Paradigm Changes In Tissue Repair-validation Of the Pbmc Secmentioning

confidence: 99%

Peripheral Blood Mononuclear Cell Secretome for Tissue Repair

Beer¹,

Mildner²,

Gyöngyösi³

et al. 2018

Cell Engineering and Regeneration

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stroke, and wound healing. In this review we describe the benefits of choosing PBMCs instead of stem cells in regenerative medicine and characterize the factors released from apoptotic PBMCs. We also discuss pre-clinical studies with apoptotic cell-based therapies and regulatory issues that have to be considered when conducting clinical trials using cell secretome-based products. This should allow the reader to envision PBMC secretome-based therapies as alternatives to all other forms of cell-based therapies.

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“…In addition, inflammation, formation of a glial scar, and chondroitin sulfate proteoglycans (CSPGs) create a hostile environment, which inhibits regeneration and CNS recovery [21][22][23]. Notably, the small GTPase RhoA does not only play a major role in axon growth during development but also during axonal regeneration [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

The brake within: Mechanisms of intrinsic regulation of axon growth featuring the Cdh1-APC pathway

Stegmüller¹

2013

Translational Neuroscience

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Neurons of the central nervous system (CNS) form a magnificent network destined to control bodily functions and human behavior for a lifetime. During development of the CNS, neurons extend axons that establish connections to other neurons. Axon growth is guided by extrinsic cues and guidance molecules. In addition to environmental signals, intrinsic programs including transcription and the ubiquitin proteasome system (UPS) have been implicated in axon growth regulation. Over the past few years it has become evident that the E3 ubiquitin ligase Cdh1-APC together with its associated pathway plays a central role in axon growth suppression. By elucidating the intricate interplay of extrinsic and intrinsic mechanisms, we can enhance our understanding of why axonal regeneration in the CNS fails and obtain further insight into how to stimulate successful regeneration after injury.

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Inflammatory Pathways in Spinal Cord Injury

Cited by 81 publications

References 104 publications

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation

Peripheral Blood Mononuclear Cell Secretome for Tissue Repair

The brake within: Mechanisms of intrinsic regulation of axon growth featuring the Cdh1-APC pathway

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