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Neural progenitors for sensory and motor repair
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi. (Regenerative Neurobiology)ORCID-id: 0000-0001-5602-0850
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested.

In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients.

Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. , s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1365
Nyckelord [en]
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury, Amyotrophic Lateral Sclerosis, Neurodegeneration, Oxidative Stress
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
Medicinsk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-328590ISBN: 978-91-513-0058-0 (tryckt)OAI: oai:DiVA.org:uu-328590DiVA, id: diva2:1137333
Disputation
2017-10-23, B/C8:305, Husargatan 3, Uppsala, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-10-02 Skapad: 2017-08-31 Senast uppdaterad: 2018-01-13
Delarbeten
1. Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
Öppna denna publikation i ny flik eller fönster >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
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2015 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikel-id 10666Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 5420, 20716
Tillgänglig från: 2015-04-20 Skapad: 2015-04-20 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
2. Sensory regeneration in dorsal root avulsion
Öppna denna publikation i ny flik eller fönster >>Sensory regeneration in dorsal root avulsion
2015 (Engelska)Ingår i: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, nr 11, s. 1739-1740Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-275487 (URN)10.4103/1673-5374.170296 (DOI)000367332800011 ()
Forskningsfinansiär
Vetenskapsrådet, 5420Vetenskapsrådet, 20716Stiftelsen Olle Engkvist Byggmästare
Tillgänglig från: 2016-02-04 Skapad: 2016-02-04 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
3. Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
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2017 (Engelska)Ingår i: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 12, nr 4, s. 339-351Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Nyckelord
calcium-binding protein, glia, nerve degeneration, neural stem cell, sensory neuron, spinal cord
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-328589 (URN)10.2217/rme-2016-0163 (DOI)000406147100006 ()28621171 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 20716
Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
4. A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (Engelska)Ingår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, nr 14, s. 1065-1077Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Nyckelord
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
Nationell ämneskategori
Neurovetenskaper Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Hematologi
Identifikatorer
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Forskningsfinansiär
Stiftelsen Olle Engkvist ByggmästareVetenskapsrådet, 20716
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
5. Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
Öppna denna publikation i ny flik eller fönster >>Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
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2017 (Engelska)Ingår i: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, nr 3, s. 773-783Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

Nyckelord
Amyotrophic lateral sclerosis, Neurodegeneration, Neuroglia, Oxidative stress, Transplantation
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-328588 (URN)10.1007/s13311-016-0505-8 (DOI)000405725300022 ()28070746 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 20716Stiftelsen Olle Engkvist Byggmästare
Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2018-09-07Bibliografiskt granskad

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