| 1. |
- Hoeber, Jan, 1986-, et al.
(författare)
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A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
- 2017
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 26:14, s. 1065-1077
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Tidskriftsartikel (refereegranskat)abstract
- Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.
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| 2. |
- König, Niclas, et al.
(författare)
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Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion
- 2017
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Ingår i: Journal of Tissue Engineering and Regenerative Medicine. - : John Wiley & Sons. - 1932-6254 .- 1932-7005. ; 11:1, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- Spinal root avulsion results in paralysis and sensory loss, and is commonly associated with chronic pain. In addition to the failure of avulsed dorsal root axons to regenerate into the spinal cord, avulsion injury leads to extensive neuroinflammation and degeneration of second order neurons in the dorsal horn. The ultimate objective with the treatment of this condition is to counteract degeneration of spinal cord neurons and to achieve functionally useful regeneration/reconnection of sensory neurons with spinal cord neurons. Here we explore if stem cells transplanted on the surface of avulsed spinal cord can survive, differentiate and migrate into the damaged spinal cord during the first few weeks after this intervention. Murine boundary cap neural crest stem cells (bNCSCs) or embryonic stem cell (ESC)-derived, pre-differentiated neuron precursors were implanted acutely at the junction between avulsed dorsal roots L3-L6 and the spinal cord. Both types of cells survived transplantation, but showed distinctly different modes of differentiation. Thus, bNCSCs migrated into the spinal cord, expressed glial markers, and formed elongated tubes in the peripheral nervous system (PNS) compartment of the avulsed dorsal root transitional zone(DRTZ) area. In contrast, the ESC-transplants remained at the site of implantation and differentiated to motor neurons and interneurons. These data show that both stem cell types successfully survive implantation to the acutely injured spinal cord and maintained their differentiation and migration potential. These data suggest that depending on the source of neural stem cells, they can play different beneficial roles for recovery after dorsal root avulsion.
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| 3. |
- Trolle, Carl, 1985-, et al.
(författare)
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Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
- 2017
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Ingår i: Regenerative Medicine. - : Future Medicine Ltd. - 1746-0751 .- 1746-076X. ; 12:4, s. 339-351
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Tidskriftsartikel (refereegranskat)abstract
- AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.
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| 4. |
- Trolle, Carl, 1985-, et al.
(författare)
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Boundary cap neural crest stem cells promote angiogenesis after transplantation to avulsed dorsal roots in mice and induce migration of endothelial cells in 3D printed scaffolds
- 2024
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 826
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Tidskriftsartikel (refereegranskat)abstract
- Dorsal root avulsion injuries lead to loss of sensation and to reorganization of blood vessels (BVs) in the injured area. The inability of injured sensory axons to re-enter the spinal cord results in permanent loss of sensation, and often also leads to the development of neuropathic pain. Approaches that restore connection between peripheral sensory axons and their CNS targets are thus urgently need. Previous research has shown that sensory axons from peripherally grafted human sensory neurons are able to enter the spinal cord by growing along BVs which penetrate the CNS from the spinal cord surface. In this study we analysed the distribution of BVs after avulsion injury and how their pattern is affected by implantation at the injury site of boundary cap neural crest stem cells (bNCSCs), a transient cluster of cells, which are located at the boundary between the spinal cord and peripheral nervous system and assist the growth of sensory axons from periphery into the spinal cord during development. The superficial dorsal spinal cord vasculature was examined using intravital microscopy and intravascular BV labelling. bNCSC transplantation increased vascular volume in a non-dose responsive manner, whereas dorsal root avulsion alone did not decrease the vascular volume. To determine whether bNCSC are endowed with angiogenic properties we prepared 3D printed scaffolds, containing bNCSCs together with rings prepared from mouse aorta. We show that bNCSC do induce migration and assembly of endothelial cells in this system. These findings suggest that bNCSC transplant can promote vascularization in vivo and contribute to BV formation in 3D printed scaffolds.
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| 5. |
- Trolle, Carl, 1985-, et al.
(författare)
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Spinal cord atrophy after spinal cord injury - A systematic review and meta-analysis
- 2023
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Ingår i: NeuroImage. - : Elsevier BV. - 2213-1582. ; 38
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Tidskriftsartikel (refereegranskat)abstract
- Cervical spinal cord atrophy occurs after spinal cord injury. The atrophy and how level of injury affects atrophy differs between studies. A systematic review and metaanalysis were done after systematic searches of PubMed, CINAHL, APA PsycInfo and Web of Science. English language original studies analyzing MRI cervical spinal cord cross-sectional area in adults with spinal cord injury were included. Atrophy and correlation between injury level and atrophy were estimated with random-effects models, standardized mean differences, and 95% confidence intervals. 24 studies were identified. 13/24 studies had low risk of bias. Cord atrophy meta-analysis of 18 articles corresponded to a standardized mean difference of -1.48 (95% CI -1.78 to -1.19) with moderate to large interstudy heterogeneity. Logarithmic time since injury influenced heterogeneity. Longitudinal atrophy was best described by a logarithmic model, indicating that rate of spinal atrophy decreases over time. Meta-correlation of eight studies indicated more severe atrophy in more rostral injuries (0.41, 95% CI 0.20-0.59). Larger and preferably longitudinal studies, data sharing, and standardized protocols are warranted.
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| 6. |
- Trolle, Carl, 1985-
(författare)
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Stem cell transplantation and regeneration after dorsal root avulsion
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spinal root avulsion leads to paralysis and loss of sensory function. Surgical methods can improve motor function and ameliorate pain but sensory recovery in adults is poor. Previous studies have shown that cell transplantation or treatment with trophic factors can improve functional outcome in rodents after dorsal root transection or crush. Here, a dorsal root injury model, more similar to human avulsion injuries, was used. The aims of this thesis were to investigate the behaviour of different stem cells following transplantation to avulsed dorsal roots and asses their potential to serve as possible regenerative therapy. In paper I, different murine stem cell types were transplanted to avulsed dorsal roots in rats. Murine embryonic stem cells remained outside the spinal cord and were surrounded by glutamatergic terminals. Boundary cap neural crest stem cells (bNCSC) formed elongated bands outside the spinal cord and migrated to the spinal cord as single cells. In paper II, transplanted bNCSC were further characterized. bNCSC remaining outside the spinal cord expressed glial markers and were associated with different types of sensory fibres. bNCSC that migrated into the injured spinal cord expressed different neuronal markers. In paper III, effects of bNCSC transplantation on local vasculature and glial scar formation were studied. bNCSC increase angiogenesis in a non dose response manner and participate in boundary glial scar formation. In paper IV, bNCSC spinal migration was analysed using two different injury models - dorsal root transection and dorsal root avulsion. In addition, bNCSC capacity to support sensory regeneration was assessed and the results suggest that bNCSC do not support robust regeneration of avulsed afferents. In paper V, an in vitro stem cell model system was used to assess the possibility of using artificial nanomaterials to deliver differentiation factors. Cells treated with either soluble factors or particle-delivered factors showed similar differentiation patterns. Stem cell transplantation offers several opportunities following dorsal root avulsion, including cell replacement and regenerative support. By elucidating the mechanisms by which stem cells can assist regeneration of avulsed afferents will allow for more targeted or combinatorial approaches, including growth factor treatment.
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| 7. |
- Trolle, Carl, 1985-
(författare)
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Stem Cell Transplantation in Dorsal Root Injury
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- After traumatic injuries to the brachial plexus there is a risk that one or more of the spinal roots are torn from the spinal cord, known as avulsion injury. This often leads to paralysis and chronic pain, notoriously difficult to treat with current pharmacotherapy. Surgical treatment may improve motor function but sensory recovery is usually poor as sensory axons fail to establish functional connections inside the spinal cord. The aims of this thesis were to develop a model for dorsal root avulsion in rodents in order to investigate the potentials of stem cell therapy for enhancing sensory regeneration after spinal root avulsion. Two different types of stem cells, embryonic and neural crest stem cells, have been transplanted to the avulsion model and analysed using immunohistochemical methods. The results indicate that stem cells survive after transplantation to the avulsed dorsal root and associate with regenerating axons. Furthermore, the different stem cells display different phenotypes after transplantation where embryonic stem cells give rise to neurons located outside the spinal cord that could serve as projection neurons whereas the neural crest stem cells form elongated tubes outlining the avulsed dorsal root and are associated with regenerating neuronal fibers. We have also discovered that the neural crest stem cells migrate into the damaged spinal cord as single cells. The neural crest stem cells also display a diversity in generating both neuronal and glial cells that may have different beneficial effects in neural repair following dorsal root avulsion. To improve the survival of stem cell transplants, the potentials of co-transplanting embryonic stem cells together with nanoparticle delivered growth factor mimetics has been investigated. The results indicate that nanoparticle delivered growth factors improve both transplant survival and maturation in comparison to untreated controls and may be a promising strategy in stem cell transplantation.
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