Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity

Hiroshi Sakai, Sumiaki Fukuda, Miki Nakamura, Akiyoshi Uezumi, Yu Taro Noguchi, Takahiko Sato, Mitsuhiro Morita, Harumoto Yamada, Kunihiro Tsuchida, Shahragim Tajbakhsh, So Ichiro Fukada

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Myogenic stem cells are a promising avenue for the treatment of muscular disorders. Freshly isolated muscle stem cells have a remarkable engraftment ability in vivo, but their cell number is limited. Current conventional culture conditions do not allow muscle stem cells to expand in vitro with their bona fide engraftment efficiency, requiring the improvement of culture procedures for achieving successful cell-therapy for muscle disorders. Here we expanded mouse muscle stem cells and human myoblasts with Notch ligands, DLL1, DLL4, and JAG1 to activate Notch signaling in vitro and to investigate whether these cells could retain their engraftment efficiency. Notch signaling promotes the expansion of Pax7+MyoDmouse muscle stem-like cells and inhibits differentiation even after passage in vitro. Treatment with Notch ligands induced the Notch target genes and generated PAX7+MYODstem- like cells from human myoblasts previously cultured on conventional culture plates. However, cells treated with Notch ligands exhibit a stem cell-like state in culture, yet their regenerative ability was less than that of freshly isolated cells in vivo and was comparable to that of the control. These unexpected findings suggest that artificial maintenance of Notch signaling alone is insufficient for improving regenerative capacity of mouse and human donor-muscle cells and suggest that combinatorial events are critical to achieve muscle stem cell and myoblast engraftment potential.

Original languageEnglish
Article numbere0177516
JournalPloS one
Volume12
Issue number5
DOIs
Publication statusPublished - 01-05-2017

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Muscle
Stem cells
Muscle Cells
Stem Cells
stem cells
Ligands
myocytes
Muscles
muscles
stems
myoblasts
Myoblasts
cells
muscular diseases
Cell culture
mice
Muscular Diseases
Cell- and Tissue-Based Therapy
ligands
Cell Differentiation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sakai, H., Fukuda, S., Nakamura, M., Uezumi, A., Noguchi, Y. T., Sato, T., ... Fukada, S. I. (2017). Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity. PloS one, 12(5), [e0177516]. https://doi.org/10.1371/journal.pone.0177516
Sakai, Hiroshi ; Fukuda, Sumiaki ; Nakamura, Miki ; Uezumi, Akiyoshi ; Noguchi, Yu Taro ; Sato, Takahiko ; Morita, Mitsuhiro ; Yamada, Harumoto ; Tsuchida, Kunihiro ; Tajbakhsh, Shahragim ; Fukada, So Ichiro. / Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity. In: PloS one. 2017 ; Vol. 12, No. 5.
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abstract = "Myogenic stem cells are a promising avenue for the treatment of muscular disorders. Freshly isolated muscle stem cells have a remarkable engraftment ability in vivo, but their cell number is limited. Current conventional culture conditions do not allow muscle stem cells to expand in vitro with their bona fide engraftment efficiency, requiring the improvement of culture procedures for achieving successful cell-therapy for muscle disorders. Here we expanded mouse muscle stem cells and human myoblasts with Notch ligands, DLL1, DLL4, and JAG1 to activate Notch signaling in vitro and to investigate whether these cells could retain their engraftment efficiency. Notch signaling promotes the expansion of Pax7+MyoDmouse muscle stem-like cells and inhibits differentiation even after passage in vitro. Treatment with Notch ligands induced the Notch target genes and generated PAX7+MYODstem- like cells from human myoblasts previously cultured on conventional culture plates. However, cells treated with Notch ligands exhibit a stem cell-like state in culture, yet their regenerative ability was less than that of freshly isolated cells in vivo and was comparable to that of the control. These unexpected findings suggest that artificial maintenance of Notch signaling alone is insufficient for improving regenerative capacity of mouse and human donor-muscle cells and suggest that combinatorial events are critical to achieve muscle stem cell and myoblast engraftment potential.",
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Sakai, H, Fukuda, S, Nakamura, M, Uezumi, A, Noguchi, YT, Sato, T, Morita, M, Yamada, H, Tsuchida, K, Tajbakhsh, S & Fukada, SI 2017, 'Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity', PloS one, vol. 12, no. 5, e0177516. https://doi.org/10.1371/journal.pone.0177516

Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity. / Sakai, Hiroshi; Fukuda, Sumiaki; Nakamura, Miki; Uezumi, Akiyoshi; Noguchi, Yu Taro; Sato, Takahiko; Morita, Mitsuhiro; Yamada, Harumoto; Tsuchida, Kunihiro; Tajbakhsh, Shahragim; Fukada, So Ichiro.

In: PloS one, Vol. 12, No. 5, e0177516, 01.05.2017.

Research output: Contribution to journalArticle

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T1 - Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity

AU - Sakai, Hiroshi

AU - Fukuda, Sumiaki

AU - Nakamura, Miki

AU - Uezumi, Akiyoshi

AU - Noguchi, Yu Taro

AU - Sato, Takahiko

AU - Morita, Mitsuhiro

AU - Yamada, Harumoto

AU - Tsuchida, Kunihiro

AU - Tajbakhsh, Shahragim

AU - Fukada, So Ichiro

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Myogenic stem cells are a promising avenue for the treatment of muscular disorders. Freshly isolated muscle stem cells have a remarkable engraftment ability in vivo, but their cell number is limited. Current conventional culture conditions do not allow muscle stem cells to expand in vitro with their bona fide engraftment efficiency, requiring the improvement of culture procedures for achieving successful cell-therapy for muscle disorders. Here we expanded mouse muscle stem cells and human myoblasts with Notch ligands, DLL1, DLL4, and JAG1 to activate Notch signaling in vitro and to investigate whether these cells could retain their engraftment efficiency. Notch signaling promotes the expansion of Pax7+MyoDmouse muscle stem-like cells and inhibits differentiation even after passage in vitro. Treatment with Notch ligands induced the Notch target genes and generated PAX7+MYODstem- like cells from human myoblasts previously cultured on conventional culture plates. However, cells treated with Notch ligands exhibit a stem cell-like state in culture, yet their regenerative ability was less than that of freshly isolated cells in vivo and was comparable to that of the control. These unexpected findings suggest that artificial maintenance of Notch signaling alone is insufficient for improving regenerative capacity of mouse and human donor-muscle cells and suggest that combinatorial events are critical to achieve muscle stem cell and myoblast engraftment potential.

AB - Myogenic stem cells are a promising avenue for the treatment of muscular disorders. Freshly isolated muscle stem cells have a remarkable engraftment ability in vivo, but their cell number is limited. Current conventional culture conditions do not allow muscle stem cells to expand in vitro with their bona fide engraftment efficiency, requiring the improvement of culture procedures for achieving successful cell-therapy for muscle disorders. Here we expanded mouse muscle stem cells and human myoblasts with Notch ligands, DLL1, DLL4, and JAG1 to activate Notch signaling in vitro and to investigate whether these cells could retain their engraftment efficiency. Notch signaling promotes the expansion of Pax7+MyoDmouse muscle stem-like cells and inhibits differentiation even after passage in vitro. Treatment with Notch ligands induced the Notch target genes and generated PAX7+MYODstem- like cells from human myoblasts previously cultured on conventional culture plates. However, cells treated with Notch ligands exhibit a stem cell-like state in culture, yet their regenerative ability was less than that of freshly isolated cells in vivo and was comparable to that of the control. These unexpected findings suggest that artificial maintenance of Notch signaling alone is insufficient for improving regenerative capacity of mouse and human donor-muscle cells and suggest that combinatorial events are critical to achieve muscle stem cell and myoblast engraftment potential.

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