Differentiation of Atrial Cardiomyocytes from Pluripotent Stem Cells Using the BMP Antagonist Grem2

Bylund, Jeffery B.; Hatzopoulos, Antonis K.

doi:10.3791/53919

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…Previous studies from other groups have shown that GREM2 is involved in proliferation and differentiation of stem cells. For example, GREM2 promotes the proliferation of myocardial progenitor cells and the differentiation of stem cells into myocytes [ [25] , [26] , [27] ]. Additionally, GREM2 suppresses the osteoblast differentiation of bone marrow-derived mesenchymal stem cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, GREM2 promotes the proliferation of myocardial progenitor cells and the differentiation of stem cells into myocytes. GREM2 is also known to suppress the differentiation of bone marrow-derived mesenchymal stem cells into osteoblasts [ [25] , [26] , [27] , [28] ]. These findings indicate that GREM2 has a great influence on the proliferation and differentiation of stem cells.…”

Section: Introductionmentioning

confidence: 99%

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Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin

Kawagishi‐Hotta

Hasegawa

Inoue

et al. 2021

Regenerative Therapy

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Introduction The skin is comprised of various kinds of cells and has three layers, the epidermis, dermis and subcutaneous adipose tissue. Stem cells in each tissue duplicate themselves and differentiate to supply new cells that function in the tissue, and thereby maintain the tissue homeostasis. In contrast, senescent cells accumulate with age and secrete senescence-associated secretory phenotype (SASP) factors that impair surrounding cells and tissues, which lowers the capacity to maintain homeostasis in each tissue. Previously, we found Gremlin 2 (GREM2) as a novel SASP factor in the skin and reported that GREM2 suppressed the differentiation of adipose-derived stromal/stem cells. In the present study, we investigated the effects of GREM2 on stem cells in the epidermis and dermis. Methods To examine whether GREM2 expression and the differentiation levels in the epidermis and dermis are correlated, the expressions of GREM2, stem cell markers, an epidermal differentiation marker Keratin 10 (KRT10) and a dermal differentiation marker type 3 procollagen were examined in the skin samples (n = 14) randomly chosen from the elderly where GREM2 expression level is high and the individual differences of its expression are prominent. Next, to test whether GREM2 affects the differentiation of skin stem cells, cells from two established lines (an epidermal and a dermal stem/progenitor cell model) were cultured and induced to differentiate, and recombinant GREM2 protein was added. Results In the human skin, the expression levels of GREM2 varied among individuals both in the epidermis and dermis. The expression level of GREM2 was not correlated with the number of stem cells, but negatively correlated with those of both an epidermal and a dermal differentiation markers. The expression levels of epidermal differentiation markers were significantly suppressed by the addition of GREM2 in the three-dimensional (3D) epidermis generated with an epidermal stem/progenitor cell model. In addition, by differentiation induction, the expressions of dermal differentiation markers were induced in cells from a dermal stem/progenitor cell model, and the addition of GREM2 significantly suppressed the expressions of the dermal differentiation markers. Conclusions GREM2 expression level did not affect the numbers of stem cells in the epidermis and dermis but affects the differentiation and maturation levels of the tissues, and GREM2 suppressed the differentiation of stem/progenitor cells in vitro . These findings suggest that GREM2 may contribute to the age-related reduction in the capacity to maintain skin homeostasis by suppressing the differentiation of epidermal and dermal stem/progenitor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin

Kawagishi‐Hotta

Hasegawa

Inoue

et al. 2021

Regenerative Therapy

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“…Grem2 is used experimentally to generate cardiomyocytes from mouse embryonic stem cells (ESCs) [18] and BMP-4 inhibits cardiomyocyte differentiation from mouse ESCs [19]. Grem2 was previously shown to induce the differentiation of embryonic stem cells into a cardiomyocyte lineage via the activation of the c-Jun N-terminal kinase pathway [20].…”

Section: Discussionmentioning

confidence: 99%

Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

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“…The expression of GREM2 was also found in adult tissues, such as the ovaries, spleen, and brain, and the activity of BMP-responsive promoters was blocked by the binding of GREM2 to BMP-2 or BMP-4 [12], [13]. Recently, GREM2 was reported to inhibit the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into osteoblasts as well as the adipogenesis of 3T3-L1 cells [9], [10], [14], [15], [16], [17]. This suggests that GREM2 plays an important role in tissue homeostasis by promoting or inhibiting the differentiation of stem cells.…”

Section: Introductionmentioning

confidence: 99%

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

Kawagishi‐Hotta

Hasegawa

Igarashi³

et al. 2019

Regenerative Therapy

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IntroductionAdipose-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.MethodsTo 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.ResultsIn 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.ConclusionsThe 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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Differentiation of Atrial Cardiomyocytes from Pluripotent Stem Cells Using the BMP Antagonist Grem2

Cited by 6 publications

References 28 publications

Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin

Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin

Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

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

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