Thymosin β4-enhancing therapeutic efficacy of human adipose-derived stem cells in mouse ischemic hindlimb model

Jong Ho Kim; I. Rang Lim; Chi Yeon Park; Hyung Joon Joo; Ji Min Noh; Seung Cheol Choi; Soon Jun Hong; Do Sun Lim

doi:10.3390/ijms21062166

Thymosin β4-enhancing therapeutic efficacy of human adipose-derived stem cells in mouse ischemic hindlimb model

Jong Ho Kim, I. Rang Lim, Chi Yeon Park, Hyung Joon Joo, Ji Min Noh, Seung Cheol Choi, Soon Jun Hong, Do Sun Lim

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7 Citations (Scopus)

Abstract

Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

Original language	English
Article number	2166
Journal	International journal of molecular sciences
Volume	21
Issue number	6
DOIs	https://doi.org/10.3390/ijms21062166
Publication status	Published - 2020 Mar 2

Bibliographical note

Funding Information:
Funding: This research was funded by National Research Foundation of Korea: NRF-2016R1A6A3A11930414; National Research Foundation of Korea: NRF-2019R1I1A1A01056103.

Funding Information:
Acknowledgments: We are grateful to Ji-Hyun Choi and Seongmin Jun for expert technical assistance. This research was supported by Korea University in 2016, by the Research Fellow Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2016R1A6A3A11930414 and NRF-2019R1I1A1A01056103), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI17C2125).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. T.

Keywords

Adipose-derived stem cells
Endothelial Differentiation
Hindlimb ischemia
Thymosin β4
Vascularization

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

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title = "Thymosin β4-enhancing therapeutic efficacy of human adipose-derived stem cells in mouse ischemic hindlimb model",

abstract = "Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.",

keywords = "Adipose-derived stem cells, Endothelial Differentiation, Hindlimb ischemia, Thymosin β4, Vascularization",

author = "Kim, {Jong Ho} and Lim, {I. Rang} and Park, {Chi Yeon} and Joo, {Hyung Joon} and Noh, {Ji Min} and Choi, {Seung Cheol} and Hong, {Soon Jun} and Lim, {Do Sun}",

note = "Funding Information: Funding: This research was funded by National Research Foundation of Korea: NRF-2016R1A6A3A11930414; National Research Foundation of Korea: NRF-2019R1I1A1A01056103. Funding Information: Acknowledgments: We are grateful to Ji-Hyun Choi and Seongmin Jun for expert technical assistance. This research was supported by Korea University in 2016, by the Research Fellow Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2016R1A6A3A11930414 and NRF-2019R1I1A1A01056103), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI17C2125). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland. T.",

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AU - Kim, Jong Ho

AU - Lim, I. Rang

AU - Park, Chi Yeon

AU - Joo, Hyung Joon

AU - Noh, Ji Min

AU - Choi, Seung Cheol

AU - Hong, Soon Jun

AU - Lim, Do Sun

N1 - Funding Information: Funding: This research was funded by National Research Foundation of Korea: NRF-2016R1A6A3A11930414; National Research Foundation of Korea: NRF-2019R1I1A1A01056103. Funding Information: Acknowledgments: We are grateful to Ji-Hyun Choi and Seongmin Jun for expert technical assistance. This research was supported by Korea University in 2016, by the Research Fellow Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2016R1A6A3A11930414 and NRF-2019R1I1A1A01056103), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI17C2125). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. T.

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N2 - Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

AB - Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

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Thymosin β4-enhancing therapeutic efficacy of human adipose-derived stem cells in mouse ischemic hindlimb model

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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