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- Berg, A., et al.
(författare)
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Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C3
- 2012
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 237:1, s. 8-17
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Tidskriftsartikel (refereegranskat)abstract
- Complement proteins C1q and C3 play a critical role in synaptic elimination during development. Axotomy of spinal motoneurons triggers removal of synaptic terminals from the cell surface of motoneurons by largely unknown mechanisms. We therefore hypothesized that the complement system is involved also in synaptic stripping of injured motoneurons. In the sciatic motor pool of wild type (WT) mice, the immunoreactivity (IR) for both C1q and C3 was increased after sciatic nerve transection (SNT). Mice deficient in C3 (C3(-/-)) showed a reduced loss of synaptic terminals from injured motoneurons at one week after SNT, as assessed by immunoreactivity for synaptic markers and electron microscopy. In particular, the removal of putative inhibitory terminals, immunopositive for vesicular inhibitory amino acid transporter (VIAAT) and ultrastructurally identified as type F synapses, was reduced in C3(-/-) mice. In contrast, lesion-induced removal of nerve terminals in C1q(-/-) mice appeared similar to WT mice. Growth associated protein (GAP)-43 mRNA expression in lesioned motoneurons increased much more in C3(-/-) compared to WT mice after SNT. After sciatic nerve crush (SNC), the C3(-/-) mice showed a faster functional recovery, assessed as grip strength, compared to WT mice. No differences were detected regarding nerve inflammation at the site of injury or pattern of muscle reinnervation. These data indicate that a non-classical pathway of complement activation is involved in axotomy-induced adult synapse removal, and that its inhibition promotes functional recovery. (c) 2012 Elsevier Inc. All rights reserved.
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- Cullheim, S, et al.
(författare)
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Classic major histocompatibility complex class I molecules: new actors at the neuromuscular junction
- 2010
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Ingår i: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. - : SAGE Publications. - 1089-4098. ; 16:6, s. 600-607
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Tidskriftsartikel (refereegranskat)abstract
- The presence and function of immune molecules in the central nervous system (CNS) have been under debate for a long time. There is mounting evidence that molecules fundamental for immune function are indeed expressed by both neurons and glia and that such molecules may have important nonimmunological function for the organization and stability of synaptic connections. Here, we present data showing that the classic form of major histocompatibility complex (MHC) class I molecules is expressed in spinal motoneurons, in particular in their axons and presynaptically at their synapses with skeletal muscles, the neuromuscular junctions (NMJs). The expression is strongly increased after axon lesion in the peripheral nerve. In the absence of classic MHC I, the organization of NMJs is disturbed with NMJs in higher numbers than normal, thereby equipping single muscle fibers with multiple NMJs. It is suggested that these effects are mediated by the classic MHC class I in the motor axons, possibly through effects mediated by the peripherally myelinating Schwann cells, which express receptors for classic MHC class I. The presence of immune molecules normally used by other cells for antigen presentation in peripheral motor axons may have implications for the onset of specific motoneuron disease.
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- Foo, Kylie S, et al.
(författare)
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Human ISL1+ ventricular progenitors self-assemble into an in vivo functional heart patch and preserve cardiac function post infarction
- 2018
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Ingår i: Molecular Therapy. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1525-0016. ; 26:7, s. 1644-1659
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Tidskriftsartikel (refereegranskat)abstract
- The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm x 3 mm x 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy. Correction in Mol Ther. 2021 Jan 6;29(1):409, DOI: 10.1016/j.ymthe.2020.11.015
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- Cheng, A, et al.
(författare)
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Increased fatigue resistance and preserved specific force in intact single muscle fibres from the SOD1G93A mouse model of ALS
- 2017
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Ingår i: Acta Physiologica. - : Wiley-Blackwell. - 1748-1708 .- 1748-1716. ; 219:S710, s. 17-17
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a motor neurone disease characterized by degeneration and loss of motor neurones, leading to severe muscle weakness and paralysis. Although motor neurone degeneration is already a well-characterized symptom that contributes to muscle weakness in the SOD1G93A mouse model of ALS, the purpose of the current study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles of SOD1G93A mice.Methods: Experiments were performed on whole muscles and mechanically dissected intact single fibres from the flexor digitorum brevis (FDB) muscle of SOD1G93A mice at three age groups of 50, 125 and 150 days of age (P50, P125 and P150). Myoplasmic free [Ca2+] ([Ca2+]i) was measured using the fluorescent indicator, indo-1.Results: Motor neurone loss and decreased force were evident in whole FDB muscles of P125–150 mice. In the intact single muscle fibres however, specific force, tetanic [Ca2+]iand resting [Ca2+]i were similar in single FDB fibres from symptomatic P125–150 SOD1G93A and age-matched wild-type littermates. The most intriguing finding was a markedly greater fatigue resistance in single fibres from P125–150 SOD1G93A vs. wild-type mice, which was not present in asymptomatic young P50 SOD1G93A mice. No shift in fibre-type distribution was observed in whole FDB muscles to explain the increased fatigue resistance of single fibres from P125–150 SOD1G93A mice.Conclusion: These results support the hypothesis that muscle weakness in ALS is not attributed to intrinsicdefects in skeletal muscle fibre force generation.
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- Foo, KS, et al.
(författare)
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Transgenic substitution with Greater Amberjack Seriola dumerili fish insulin 2 in NOD mice reduces beta cell immunogenicity
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 4965-
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Tidskriftsartikel (refereegranskat)abstract
- Type I diabetes (T1D) is caused by immune-mediated destruction of pancreatic beta cells. This process is triggered, in part, by specific (aa 9–23) epitopes of the insulin Β chain. Previously, fish insulins were used clinically in patients allergic to bovine or porcine insulin. Fish and human insulin differ by two amino acids in the critical immunogenic region (aa 9–23) of the B chain. We hypothesized that β cells synthesizing fish insulin would be less immunogenic in a mouse model of T1D. Transgenic NOD mice in which Greater Amberjack fish (Seriola dumerili) insulin was substituted for the insulin 2 gene were generated (mouse Ins1−/− mouse Ins2−/− fish Ins2+/+). In these mice, pancreatic islets remained free of autoimmune attack. To determine whether such reduction in immunogenicity is sufficient to protect β cells from autoimmunity upon transplantation, we transplanted fish Ins2 transgenic (expressing solely Seriola dumerili Ins2), NOD, or B16:A-dKO islets under the kidney capsules of 5 weeks old female NOD wildtype mice. The B:Y16A Β chain substitution has been previously shown to be protective of T1D in NOD mice. NOD mice receiving Seriola dumerili transgenic islet transplants showed a significant (p = 0.004) prolongation of their euglycemic period (by 6 weeks; up to 18 weeks of age) compared to un-manipulated female NOD (diabetes onset at 12 weeks of age) and those receiving B16:A-dKO islet transplants (diabetes onset at 12 weeks of age). These data support the concept that specific amino acid sequence modifications can reduce insulin immunogenicity. Additionally, our study shows that alteration of a single epitope is not sufficient to halt an ongoing autoimmune response. Which, and how many, T cell epitopes are required and suffice to perpetuate autoimmunity is currently unknown. Such studies may be useful to achieve host tolerance to β cells by inactivating key immunogenic epitopes of stem cell-derived β cells intended for transplantation.
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