Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis

Mika Kawagishi-Hotta, Seiji Hasegawa, Toshio Igarashi, Yasushi Date, Yoshie Ishii, Yu Inoue, Yuichi Hasebe, Takaaki Yamada, Masaru Arima, Yohei Iwata, Tsukane Kobayashi, Satoru Nakata, Kazumitsu Sugiura, Hirohiko Akamatsu

Research output: Contribution to journalArticle

Abstract

Introduction: Adipose-derived stromal/stem cells (ASCs) have attracted attention as a promising material for regenerative medicine. Previously, we reported an age-related decrease in the adipogenic potential of ASCs from human subjects and found that the individual difference in this potential increased with age, although the mechanisms remain unclear. Recently, other groups demonstrated that a secreted antagonist of bone morphogenetic protein (BMP) signaling, Gremlin 2 (GREM2), inhibits the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts and the adipogenesis of 3T3-L1 cell. Here, we examined the effects of GREM2 on the differentiation of ASCs into adipocytes. Methods: To examine changes in GREM2 expression levels with age, immunohistochemistry was performed on subcutaneous adipose tissues from subjects 12–97 years of age. Next, GREM2 gene expression levels in ASCs collected from subjects 5–90 years of age were examined by RT-PCR, and the change with age and correlation between the expression level and the adipogenic potential of ASCs were analyzed. In addition, to assess whether GREM2 affects adipogenesis, ASCs (purchased from a vendor) were cultured to induce adipogenesis with recombinant GREM2 protein, and siRNA-induced GREM2 knockdown experiment was also performed using aged ASCs. Results: In adipose tissues, GREM2 expression was observed in cells, including ASCs, but not in mature adipocytes, and the expression level per cell increased with age. GREM2 expression levels in ASCs cultured in vitro also increased with age, and the individual differences in the level increased with age. Of note, partial correlation analysis controlled for age revealed that the adipogenic potential of ASCs and the GREM2 gene expression level were negatively correlated. Furthermore, based on a GREM2 addition experiment, GREM2 has inhibitory effects on the adipogenesis of ASCs through activation of Wnt/β-catenin signaling. On the other hand, GREM2 knockdown in aged ASCs promoted adipogenesis. Conclusions: The GREM2 expression level was confirmed to play a role in the age-related decrease in adipogenic potential observed in ASCs isolated from adipose tissues as well as in the enhancement of the individual difference, which increased with age. GREM2 in adipose tissues increased with age, which suggested that GREM2 functions as an inhibitory factor of adipogenesis in ASCs.

Original languageEnglish
Pages (from-to)324-330
Number of pages7
JournalRegenerative Therapy
Volume11
DOIs
Publication statusPublished - 12-2019

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Adipogenesis
Stromal Cells
Stem cells
Stem Cells
Individuality
Adipose Tissue
Tissue
Adipocytes
Gene expression
Bone
Interleukin-11
3T3-L1 Cells
Gene Expression
Catenins
Proteins
Bone Morphogenetic Proteins
Regenerative Medicine
Subcutaneous Fat
Osteoblasts
Mesenchymal Stromal Cells

All Science Journal Classification (ASJC) codes

  • Biomaterials
  • Biomedical Engineering
  • Developmental Biology

Cite this

Kawagishi-Hotta, M., Hasegawa, S., Igarashi, T., Date, Y., Ishii, Y., Inoue, Y., ... Akamatsu, H. (2019). Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis. Regenerative Therapy, 11, 324-330. https://doi.org/10.1016/j.reth.2019.09.002
Kawagishi-Hotta, Mika ; Hasegawa, Seiji ; Igarashi, Toshio ; Date, Yasushi ; Ishii, Yoshie ; Inoue, Yu ; Hasebe, Yuichi ; Yamada, Takaaki ; Arima, Masaru ; Iwata, Yohei ; Kobayashi, Tsukane ; Nakata, Satoru ; Sugiura, Kazumitsu ; Akamatsu, Hirohiko. / Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis. In: Regenerative Therapy. 2019 ; Vol. 11. pp. 324-330.
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abstract = "Introduction: Adipose-derived stromal/stem cells (ASCs) have attracted attention as a promising material for regenerative medicine. Previously, we reported an age-related decrease in the adipogenic potential of ASCs from human subjects and found that the individual difference in this potential increased with age, although the mechanisms remain unclear. Recently, other groups demonstrated that a secreted antagonist of bone morphogenetic protein (BMP) signaling, Gremlin 2 (GREM2), inhibits the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts and the adipogenesis of 3T3-L1 cell. Here, we examined the effects of GREM2 on the differentiation of ASCs into adipocytes. Methods: To examine changes in GREM2 expression levels with age, immunohistochemistry was performed on subcutaneous adipose tissues from subjects 12–97 years of age. Next, GREM2 gene expression levels in ASCs collected from subjects 5–90 years of age were examined by RT-PCR, and the change with age and correlation between the expression level and the adipogenic potential of ASCs were analyzed. In addition, to assess whether GREM2 affects adipogenesis, ASCs (purchased from a vendor) were cultured to induce adipogenesis with recombinant GREM2 protein, and siRNA-induced GREM2 knockdown experiment was also performed using aged ASCs. Results: In adipose tissues, GREM2 expression was observed in cells, including ASCs, but not in mature adipocytes, and the expression level per cell increased with age. GREM2 expression levels in ASCs cultured in vitro also increased with age, and the individual differences in the level increased with age. Of note, partial correlation analysis controlled for age revealed that the adipogenic potential of ASCs and the GREM2 gene expression level were negatively correlated. Furthermore, based on a GREM2 addition experiment, GREM2 has inhibitory effects on the adipogenesis of ASCs through activation of Wnt/β-catenin signaling. On the other hand, GREM2 knockdown in aged ASCs promoted adipogenesis. Conclusions: The GREM2 expression level was confirmed to play a role in the age-related decrease in adipogenic potential observed in ASCs isolated from adipose tissues as well as in the enhancement of the individual difference, which increased with age. GREM2 in adipose tissues increased with age, which suggested that GREM2 functions as an inhibitory factor of adipogenesis in ASCs.",
author = "Mika Kawagishi-Hotta and Seiji Hasegawa and Toshio Igarashi and Yasushi Date and Yoshie Ishii and Yu Inoue and Yuichi Hasebe and Takaaki Yamada and Masaru Arima and Yohei Iwata and Tsukane Kobayashi and Satoru Nakata and Kazumitsu Sugiura and Hirohiko Akamatsu",
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Kawagishi-Hotta, M, Hasegawa, S, Igarashi, T, Date, Y, Ishii, Y, Inoue, Y, Hasebe, Y, Yamada, T, Arima, M, Iwata, Y, Kobayashi, T, Nakata, S, Sugiura, K & Akamatsu, H 2019, 'Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis', Regenerative Therapy, vol. 11, pp. 324-330. https://doi.org/10.1016/j.reth.2019.09.002

Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis. / Kawagishi-Hotta, Mika; Hasegawa, Seiji; Igarashi, Toshio; Date, Yasushi; Ishii, Yoshie; Inoue, Yu; Hasebe, Yuichi; Yamada, Takaaki; Arima, Masaru; Iwata, Yohei; Kobayashi, Tsukane; Nakata, Satoru; Sugiura, Kazumitsu; Akamatsu, Hirohiko.

In: Regenerative Therapy, Vol. 11, 12.2019, p. 324-330.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increase of gremlin 2 with age in human adipose-derived stromal/stem cells and its inhibitory effect on adipogenesis

AU - Kawagishi-Hotta, Mika

AU - Hasegawa, Seiji

AU - Igarashi, Toshio

AU - Date, Yasushi

AU - Ishii, Yoshie

AU - Inoue, Yu

AU - Hasebe, Yuichi

AU - Yamada, Takaaki

AU - Arima, Masaru

AU - Iwata, Yohei

AU - Kobayashi, Tsukane

AU - Nakata, Satoru

AU - Sugiura, Kazumitsu

AU - Akamatsu, Hirohiko

PY - 2019/12

Y1 - 2019/12

N2 - Introduction: Adipose-derived stromal/stem cells (ASCs) have attracted attention as a promising material for regenerative medicine. Previously, we reported an age-related decrease in the adipogenic potential of ASCs from human subjects and found that the individual difference in this potential increased with age, although the mechanisms remain unclear. Recently, other groups demonstrated that a secreted antagonist of bone morphogenetic protein (BMP) signaling, Gremlin 2 (GREM2), inhibits the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts and the adipogenesis of 3T3-L1 cell. Here, we examined the effects of GREM2 on the differentiation of ASCs into adipocytes. Methods: To examine changes in GREM2 expression levels with age, immunohistochemistry was performed on subcutaneous adipose tissues from subjects 12–97 years of age. Next, GREM2 gene expression levels in ASCs collected from subjects 5–90 years of age were examined by RT-PCR, and the change with age and correlation between the expression level and the adipogenic potential of ASCs were analyzed. In addition, to assess whether GREM2 affects adipogenesis, ASCs (purchased from a vendor) were cultured to induce adipogenesis with recombinant GREM2 protein, and siRNA-induced GREM2 knockdown experiment was also performed using aged ASCs. Results: In adipose tissues, GREM2 expression was observed in cells, including ASCs, but not in mature adipocytes, and the expression level per cell increased with age. GREM2 expression levels in ASCs cultured in vitro also increased with age, and the individual differences in the level increased with age. Of note, partial correlation analysis controlled for age revealed that the adipogenic potential of ASCs and the GREM2 gene expression level were negatively correlated. Furthermore, based on a GREM2 addition experiment, GREM2 has inhibitory effects on the adipogenesis of ASCs through activation of Wnt/β-catenin signaling. On the other hand, GREM2 knockdown in aged ASCs promoted adipogenesis. Conclusions: The GREM2 expression level was confirmed to play a role in the age-related decrease in adipogenic potential observed in ASCs isolated from adipose tissues as well as in the enhancement of the individual difference, which increased with age. GREM2 in adipose tissues increased with age, which suggested that GREM2 functions as an inhibitory factor of adipogenesis in ASCs.

AB - Introduction: Adipose-derived stromal/stem cells (ASCs) have attracted attention as a promising material for regenerative medicine. Previously, we reported an age-related decrease in the adipogenic potential of ASCs from human subjects and found that the individual difference in this potential increased with age, although the mechanisms remain unclear. Recently, other groups demonstrated that a secreted antagonist of bone morphogenetic protein (BMP) signaling, Gremlin 2 (GREM2), inhibits the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts and the adipogenesis of 3T3-L1 cell. Here, we examined the effects of GREM2 on the differentiation of ASCs into adipocytes. Methods: To examine changes in GREM2 expression levels with age, immunohistochemistry was performed on subcutaneous adipose tissues from subjects 12–97 years of age. Next, GREM2 gene expression levels in ASCs collected from subjects 5–90 years of age were examined by RT-PCR, and the change with age and correlation between the expression level and the adipogenic potential of ASCs were analyzed. In addition, to assess whether GREM2 affects adipogenesis, ASCs (purchased from a vendor) were cultured to induce adipogenesis with recombinant GREM2 protein, and siRNA-induced GREM2 knockdown experiment was also performed using aged ASCs. Results: In adipose tissues, GREM2 expression was observed in cells, including ASCs, but not in mature adipocytes, and the expression level per cell increased with age. GREM2 expression levels in ASCs cultured in vitro also increased with age, and the individual differences in the level increased with age. Of note, partial correlation analysis controlled for age revealed that the adipogenic potential of ASCs and the GREM2 gene expression level were negatively correlated. Furthermore, based on a GREM2 addition experiment, GREM2 has inhibitory effects on the adipogenesis of ASCs through activation of Wnt/β-catenin signaling. On the other hand, GREM2 knockdown in aged ASCs promoted adipogenesis. Conclusions: The GREM2 expression level was confirmed to play a role in the age-related decrease in adipogenic potential observed in ASCs isolated from adipose tissues as well as in the enhancement of the individual difference, which increased with age. GREM2 in adipose tissues increased with age, which suggested that GREM2 functions as an inhibitory factor of adipogenesis in ASCs.

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