Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number

Julien Rossignol, Kyle Fink, Andrew T. Crane, Kendra K. Davis, Matthew C. Bombard, Steven Clerc, Angela M. Bavar, Steven A. Lowrance, Cheng Song, Steven Witte, Laurent Lescaudron, Gary L. Dunbar

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Introduction: Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation. Methods: In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. Results: It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs. Conclusion: The results from this study demonstrate that BM MSCs hold significant therapeutic value for HD, and that the amount of time the cells are exposed to in vitro culture conditions can alter their efficacy.

Original languageEnglish (US)
Article number9
JournalStem Cell Research and Therapy
Volume6
Issue number1
DOIs
StatePublished - Feb 19 2015
Externally publishedYes

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Huntington Disease
Stem cells
Bone Marrow Transplantation
Mesenchymal Stromal Cells
Bone
Transplants
Transplantation
Bone Marrow
Neostriatum
Chromosomes, Human, Pair 4
Brain-Derived Neurotrophic Factor
Chromosomes
Neurons
Cell Count
Genes
Neuropathology
Messenger RNA
Therapeutics

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology

Cite this

Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number. / Rossignol, Julien; Fink, Kyle; Crane, Andrew T.; Davis, Kendra K.; Bombard, Matthew C.; Clerc, Steven; Bavar, Angela M.; Lowrance, Steven A.; Song, Cheng; Witte, Steven; Lescaudron, Laurent; Dunbar, Gary L.

In: Stem Cell Research and Therapy, Vol. 6, No. 1, 9, 19.02.2015.

Research output: Contribution to journalArticle

Rossignol, Julien ; Fink, Kyle ; Crane, Andrew T. ; Davis, Kendra K. ; Bombard, Matthew C. ; Clerc, Steven ; Bavar, Angela M. ; Lowrance, Steven A. ; Song, Cheng ; Witte, Steven ; Lescaudron, Laurent ; Dunbar, Gary L. / Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number. In: Stem Cell Research and Therapy. 2015 ; Vol. 6, No. 1.
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abstract = "Introduction: Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation. Methods: In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. Results: It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs. Conclusion: The results from this study demonstrate that BM MSCs hold significant therapeutic value for HD, and that the amount of time the cells are exposed to in vitro culture conditions can alter their efficacy.",
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T1 - Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number

AU - Rossignol, Julien

AU - Fink, Kyle

AU - Crane, Andrew T.

AU - Davis, Kendra K.

AU - Bombard, Matthew C.

AU - Clerc, Steven

AU - Bavar, Angela M.

AU - Lowrance, Steven A.

AU - Song, Cheng

AU - Witte, Steven

AU - Lescaudron, Laurent

AU - Dunbar, Gary L.

PY - 2015/2/19

Y1 - 2015/2/19

N2 - Introduction: Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation. Methods: In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. Results: It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs. Conclusion: The results from this study demonstrate that BM MSCs hold significant therapeutic value for HD, and that the amount of time the cells are exposed to in vitro culture conditions can alter their efficacy.

AB - Introduction: Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation. Methods: In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. Results: It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs. Conclusion: The results from this study demonstrate that BM MSCs hold significant therapeutic value for HD, and that the amount of time the cells are exposed to in vitro culture conditions can alter their efficacy.

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