YAP as a key regulator of adipo-osteogenic differentiation in human MSCs

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Abstract

Background

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into several cell types, including cartilage, fat, and bone. As a common progenitor, MSC differentiation has to be tightly regulated to maintain the balance of their differentiation commitment. It has been reported that the decision process of MSCs into fat and bone cells is competing and reciprocal. Several factors have been suggested as critical factors that affect adipo-osteogenic decision, including melatonin and smad4. Yes-associated protein (YAP) is an important effector protein in the Hippo signaling pathway that acts as a transcriptional regulator by activating the transcription of the genes involved in cell proliferation and anti-apoptosis. The non-canonical role of YAP in regulating bone homeostasis by promoting osteogenesis and suppressing adipogenesis was recently demonstrated in a mouse model. However, it is unclear whether YAP is also crucial for modulating human MSC differentiation to fat and bone.

Methods

The expression level of YAP during MSC differentiation was modulated using pharmaceutical molecule and genetic experiments through gain- and loss-of-function approaches.

Results

We demonstrated for the first time that YAP has a non-canonical role in regulating the balance of adipo-osteogenic differentiation of human MSCs. The result from synchrotron radiation-based Fourier transform infrared (FTIR) microspectroscopy showed unique metabolic fingerprints generated from YAP-targeted differentiated cells that were clearly distinguished from non-manipulated control.

Conclusions

These results, thus, identify YAP as an important effector protein that regulates human MSC differentiation to fat and bone and suggests the use of FTIR microspectroscopy as a promising technique in stem cell research.

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Most cited references 28

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Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

George Chen, P Shou, C. Zheng … (2016)

Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.

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Using Fourier transform IR spectroscopy to analyze biological materials.

Matthew J Baker, Júlio Trevisan, Paul Bassan … (2014)

IR spectroscopy is an excellent method for biological analyses. It enables the nonperturbative, label-free extraction of biochemical information and images toward diagnosis and the assessment of cell functionality. Although not strictly microscopy in the conventional sense, it allows the construction of images of tissue or cell architecture by the passing of spectral data through a variety of computational algorithms. Because such images are constructed from fingerprint spectra, the notion is that they can be an objective reflection of the underlying health status of the analyzed sample. One of the major difficulties in the field has been determining a consensus on spectral pre-processing and data analysis. This manuscript brings together as coauthors some of the leaders in this field to allow the standardization of methods and procedures for adapting a multistage approach to a methodology that can be applied to a variety of cell biological questions or used within a clinical setting for disease screening or diagnosis. We describe a protocol for collecting IR spectra and images from biological samples (e.g., fixed cytology and tissue sections, live cells or biofluids) that assesses the instrumental options available, appropriate sample preparation, different sampling modes as well as important advances in spectral data acquisition. After acquisition, data processing consists of a sequence of steps including quality control, spectral pre-processing, feature extraction and classification of the supervised or unsupervised type. A typical experiment can be completed and analyzed within hours. Example results are presented on the use of IR spectra combined with multivariate data processing.

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Effects of obesity on bone metabolism

Jay Cao (2011)

Obesity is traditionally viewed to be beneficial to bone health because of well-established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up-regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index ≥ 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health [1]. The rates of obesity rates have doubled since 1980 [2] and as of 2007, 33% of men and 35% of women in the US are obese [3]. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers [4-6]. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year [7]. Bone mass and strength decrease during adulthood, especially in women after menopause [8]. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease [9]. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell [10] and agents inhibiting adipogenesis stimulated osteoblast differentiation [11-13] and vice versa, those inhibiting osteoblastogenesis increased adipogenesis [14]. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis [15,16]. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss [17,18]. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines [19,20]. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.

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Author and article information

Contributors

Chanchao Lorthongpanich:

ORCID: http://orcid.org/0000-0003-2206-7065

chanchao.lor@mahidol.ac.th

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 18 December 2019

Publication date PMC-release: 18 December 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 402

Affiliations

[1 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, , Mahidol University, ; 2 Wanglang Road, Bangkoknoi, Bangkok, 10700 Thailand

[2 ]GRID grid.472685.a, Synchrotron Light Research Institute (Public Organization), ; Nakhon Ratchasima, Thailand

[3 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Department of Immunology, Faculty of Medicine Siriraj Hospital, , Mahidol University, ; Bangkok, Thailand

[4 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, , Mahidol University, ; Bangkok, Thailand

[5 ]Bangkok Hematology Center, Wattanosoth Hospital, BDMS Center of Excellence for Cancer, Bangkok, Thailand

Author information

Chanchao Lorthongpanich http://orcid.org/0000-0003-2206-7065

Article

Publisher ID: 1494

DOI: 10.1186/s13287-019-1494-4

PMC ID: 6921580

PubMed ID: 31852542

SO-VID: 46c056dc-34eb-4891-af48-4a9239c7da47

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 August 2019

Date revision received : 28 October 2019

Date accepted : 13 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004396, Thailand Research Fund;

Award ID: RSA-6080089

Award ID: RTA 488-0007

Award Recipient : Chanchao Lorthongpanich Surapol Issaragrisil

Funded by: FundRef http://dx.doi.org/10.13039/501100013238, Faculty of Medicine Siriraj Hospital, Mahidol University;

Award ID: n/a

Award Recipient : Chanchao Lorthongpanich

Funded by: FundRef http://dx.doi.org/10.13039/100012527, Office of the Higher Education Commission;

Award ID: CHE-RES-RG-49

Award Recipient : Surapol Issaragrisil

Funded by: FundRef http://dx.doi.org/10.13039/501100012309, Royal Golden Jubilee (RGJ) Ph.D. Programme;

Award ID: PHD/0102/2559

Award Recipient : Nattaya Damkham Surapol Issaragrisil

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: ftir microspectroscopy,dobutamine,lpa,mscs,adipo-osteogenic balance,yap,hippo pathway

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: ftir microspectroscopy, dobutamine, lpa, mscs, adipo-osteogenic balance, yap, hippo pathway

YAP as a key regulator of adipo-osteogenic differentiation in human MSCs

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Abstract

Background

Methods

Results

Conclusions

Related collections

Bacterial extracellular vesicles

Most cited references 28

Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

Using Fourier transform IR spectroscopy to analyze biological materials.

Effects of obesity on bone metabolism

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Contributors

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