Adipose-derived stem cell conditioned medium impacts asymptomatic peripheral neuromuscular denervation in the mutant superoxide dismutase (G93A) transgenic mouse model of amyotrophic lateral sclerosis

Walker, Chandler L.; Meadows, Rena M.; Merfeld-Clauss, Stephanie; Du, Yansheng; March, Keith L.; Jones, Kathryn J.

doi:10.3233/rnn-180820

Cited by 7 publications

(13 citation statements)

References 36 publications

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“…Sustaining muscle mass depends heavily on innervation and neural stimulation of NMJs. As mentioned, hindlimb skeletal muscle is significantly denervated by post-natal day 47 in the mSOD1 G93A mouse 5,6 , and our findings in the present study indicate that Akt signaling and cell degradation-associated processes including autophagosome and lysosome aggregation and increased muscle atrophy are low during and through this period. However, these processes, as indicated by LC3 lipidation, LAMP-1 and MuRF-1 expression, respectively, significantly increase at later stages of disease when Akt signaling is greatly decreased.…”

Section: Discussionsupporting

confidence: 79%

“…Much evidence suggests at least in mSOD1 G93A mutation-associated ALS, many pathologic changes in target skeletal muscle occur before symptom onset and motor neuron loss. In the mSOD1 G93A mouse model, a decrease in hindlimb muscle fiber size is noticeable between postnatal weeks eight & nine 29 , which follows closely after initial significant muscle denervation in this muscle group 5,6 . Early neuromuscular denervation triggers compensatory sprouting of motor axons, and ultimately, progresses toward disconnection from skeletal muscle.…”

Section: Discussionmentioning

confidence: 88%

“…For muscle tissue collection and immunofluorescence labeling, previously published methods were used 6 . In brief, end-stage wild-type (WT) and mSOD1 G93A mice (n = 3/group) were sacrificed using ketamine/xylazine, and perfused with 0.1 M phosphate buffered saline (PBS) followed by 4% paraformaldehyde solution in PBS to fix the tissue.…”

Section: Methodsmentioning

confidence: 99%

“…As a result of reduced motor stimulation in ALS progression, skeletal muscles atrophy and multiple biochemical processes in skeletal muscle cells have been implicated in this process. Since skeletal muscle is peripheral and directly affected early in ALS progression 5,6,9–11 , assessment of biochemical changes in animal models and human ALS for identification of potential markers of disease has increased in interest. Recent research indicated that a reduction in insulin signaling and expression and activity the serine-threonine kinase, Akt, are associated with progressive muscular atrophy in animal models and correlated with poor survival prognosis in ALS patients 12–14 .…”

Section: Introductionmentioning

confidence: 99%

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Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis

Wang¹,

Fry²,

Walker³

2019

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease involving motor neuron death, paralysis and, ultimately, respiratory failure. Motor neuron dysfunction leads to target skeletal muscle atrophy involving dysregulation of downstream cell survival, growth and metabolic signaling. Decreased Akt activity is linked to muscle atrophy in ALS and is associated with increased atrophy gene expression. Unfortunately, the regulating mechanism of Akt activity in atrophic muscle remains unclear. Recent research indicates a role of carboxyl-terminal modulator protein (CTMP) in Akt-signaling related neurologic dysfunction and skeletal muscle metabolism. CTMP is known to bind and reduce Akt phosphorylation and activation. We hypothesized that CTMP expression might progressively increase in ALS skeletal muscle as the disease progresses, downregulating Akt activity. We found that CTMP protein expression significantly increased in hindlimb skeletal muscle in the mSOD1 G93A mouse model of ALS in late stages of the disease ( P < 0.05), which negatively correlated with Akt phosphorylation over this period ( R 2 = −0.77). Co-immunoprecipitation of Akt revealed CTMP binding in pre-symptomatic and end-stage skeletal muscle, suggesting a possible direct role in reduced Akt signaling during disease progression. Inflammatory TNFα and downstream cellular degradation process markers for autophagy, lysosome production, and atrophy significantly increased in a pattern corresponding to increased CTMP expression and reduced Akt phosphorylation. In an in vitro model of skeletal muscle atrophy, differentiated C2C12 cells exhibited reduced Akt activity and decreased FOXO1 phosphorylation, a process known to promote transcription of atrophy genes in skeletal muscle. These results corresponded with increased Atrogin-1 expression compared to healthy control cells ( P < 0.05). Transfection with CTMP siRNA significantly increased Akt phosphorylation in atrophic C2C12 cells, corresponding to significantly decreased CTMP expression. In conclusion, this is the first study to provide evidence for a link between elevated CTMP expression, downregulated Akt phosphorylation and muscle atrophy in ALS and clearly demonstrates a direct influence of CTMP on Akt phosphorylation in an in vitro muscle cell atrophy model.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis

Wang¹,

Fry²,

Walker³

2019

Sci Rep

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“…Our recent research and that of our colleagues demonstrated the therapeutic potential of systemic administration of conditioned medium containing the trophic and other secretions from human adipose-derived stem/stromal cell cultures (ASC-CM). We showed that early pre-symptomatic treatment with ASC-CM reduced early NMJ denervation when administered before and during this early disease component [11]. Our colleagues previously demonstrated the post-symptomatic benefits of ASC-CM on spinal cord astrogliosis, MN survival and overall lifespan in the mSOD1 G93A mouse [12].…”

Section: Introductionmentioning

confidence: 99%

Systemic Dental Pulp Stem Cell Secretome Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis

2019

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Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron (MN) disease with no cure. Accumulating evidence indicates ALS involves a complex interaction between central glia and the peripheral immune response and neuromuscular interface. Stem cell secretomes contain various beneficial trophic factors and cytokines, and we recently demonstrated that administration of the secretome of adipose-derived stem cells (ASCs) during early neuromuscular junction (NMJ) denervation in the mutant superoxide dismutase (mSOD1G93A) ALS mouse ameliorated NMJ disruption. In the present study, we hypothesized that administration of dental pulp stem cell secretome in the form of conditioned medium (DPSC-CM) at different stages of disease would promote NMJ innervation, prevent MN loss and extend lifespan. Our findings show that DPSC-CM significantly improved NMJ innervation at postnatal day (PD) 47 compared to vehicle treated mSOD1G93A mice (p < 0.05). During late pre-symptomatic stages (PD70-P91), DPSC-CM significantly increased MN survival (p < 0.01) and NMJ preservation (p < 0.05), while reactive gliosis in the ventral horn remained unaffected. For DPSC-CM treated mSOD1G93A mice beginning at symptom onset, post-onset days of survival as well as overall lifespan was significantly increased compared to vehicle treated mice (p < 0.05). This is the first study to show therapeutic benefits of systemic DPSC secretome in experimental ALS, and establishes a foundation for future research into the treatment effects and mechanistic analyses of DPSC and other stem cell secretome therapies in ALS.

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Adipose stem cell secretome markedly improves rodent heart and human induced pluripotent stem cell-derived cardiomyocyte recovery from cardioplegic transport solution exposure

et al. 2020

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Heart transplantation is a life-saving therapy for end-stage organ failure. Organ deterioration during transportation limits storage to 4 hours, limiting hearts available. Approaches ameliorating organ damage could increase the number of hearts acceptable for transplantation. Prior studies show that adipose-derived stem/stromal cell secretome (ASC-S) rescues tissues from postischemic damage in vivo. This study tested whether ASC-S preserved the function of mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes (iCM) exposed to organ transportation and transplantation conditions. Hearts were subjected to cold University of Wisconsin (UW) cardioplegic solution ± ASC-S for 6 hours followed by analysis using the Langendorff technique. In parallel, the effects of ASC-S on the recovery of iCM from UW solution were examined when provided either during or after cold cardioplegia. Exposure of hearts and iCM to UW deteriorated contractile activity and caused cell apoptosis, worsening in iCM as a function of exposure time; these were ameliorated by augmenting with ASC-S. Silencing of superoxide dismutase 3 and catalase expression prior to secretome generation compromised the ASC-S cardiomyocyte-protective effects. In this study, a novel in vitro iCM model was developed to complement a rodent heart model in assessing efficacy of approaches to improve cardiac preservation. ASC-S displays strong cardioprotective activity on iCM either with or following cold cardioplegia. This effect is associated with ASC-S-mediated cellular clearance of reactive oxygen species. The effect of ASC-S on the temporal recovery of iCM function supports the possibility of lengthening heart storage by augmenting cardioplegic transport solution with ASC-S, expanding the pool of hearts for transplantation.

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Adipose-derived stem cell conditioned medium impacts asymptomatic peripheral neuromuscular denervation in the mutant superoxide dismutase (G93A) transgenic mouse model of amyotrophic lateral sclerosis

Abstract: Our results lay the foundation for testing the long-term neurological benefits of systemic ASC-CM therapy in the mSOD1G93A mouse model of ALS.

Cited by 7 publications

References 36 publications

Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis

Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis

Systemic Dental Pulp Stem Cell Secretome Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis

Adipose stem cell secretome markedly improves rodent heart and human induced pluripotent stem cell-derived cardiomyocyte recovery from cardioplegic transport solution exposure

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