An Adenosine Receptor-Krüppel-like Factor 4 Protein Axis Inhibits Adipogenesis

Eisenstein, Anna; Carroll, Shannon H.; Johnston-Cox, Hillary; Farb, Melissa G.; Gokce, Noyan; Ravid, Katya

doi:10.1074/jbc.m114.566406

Cited by 32 publications

(26 citation statements)

References 71 publications

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“…KDLER1 codes for an endoplasmic reticulum (ER) receptor involved in the retention of resident soluble proteins in the ER lumen, and interacts with MAPKAP kinase MK2 to maintain the self‐renewal capacity of hematopoietic stem cells . KLF4 is a member of the four stemness (“Yamanaka”) factors and along with MYC controls adipogenesis in ASCs . KLF4 also possesses other roles in vascularization along with KLF6 .…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Networks in Single Perivascular Cells Sorted from Human Adipose Tissue Reveal a Hierarchy of Mesenchymal Stem Cells

Hardy

Moldovan

et al. 2017

Stem Cells

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Adipose tissue is a rich source of multipotent mesenchymal stem-like cells, located in the perivascular niche. Based on their surface markers, these have been assigned to two main categories: CD31 /CD45 /CD34 /CD146 cells (adventitial stromal/stem cells [ASCs]) and CD31 /CD45 /CD34 /CD146 cells (pericytes [PCs]). These populations display heterogeneity of unknown significance. We hypothesized that aldehyde dehydrogenase (ALDH) activity, a functional marker of primitivity, could help to better define ASC and PC subclasses. To this end, the stromal vascular fraction from a human lipoaspirate was simultaneously stained with fluorescent antibodies to CD31, CD45, CD34, and CD146 antigens and the ALDH substrate Aldefluor, then sorted by fluorescence-activated cell sorting. Individual ASCs (n = 67) and PCs (n = 73) selected from the extremities of the ALDH-staining spectrum were transcriptionally profiled by Fluidigm single-cell quantitative polymerase chain reaction for a predefined set (n = 429) of marker genes. To these single-cell data, we applied differential expression and principal component and clustering analysis, as well as an original gene coexpression network reconstruction algorithm. Despite the stochasticity at the single-cell level, covariation of gene expression analysis yielded multiple network connectivity parameters suggesting that these perivascular progenitor cell subclasses possess the following order of maturity: (a) ALDH ASC (most primitive); (b) ALDH ASC; (c) ALDH PC; (d) ALDH PC (least primitive). This order was independently supported by specific combinations of class-specific expressed genes and further confirmed by the analysis of associated signaling pathways. In conclusion, single-cell transcriptional analysis of four populations isolated from fat by surface markers and enzyme activity suggests a developmental hierarchy among perivascular mesenchymal stem cells supported by markers and coexpression networks. Stem Cells 2017;35:1273-1289.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Networks in Single Perivascular Cells Sorted from Human Adipose Tissue Reveal a Hierarchy of Mesenchymal Stem Cells

Hardy

Moldovan

et al. 2017

Stem Cells

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“…44,45 Findings in a recent study by Eisenstein et al further demonstrate that A2bR activation inhibits adipogenic differentiation of preadipocytes through the transcription factor Krüppel-like factor 4 (KLF4), which appears to be partially regulated by an increase in cAMP and activation of PKA. 46 However, other studies have shown that KLF4 directly binds CCAAT/enhancer-binding protein β (C/EBP β ) promoter and is required for adipogenesis, 47 whereas ectopic overexpression of KLF4 attenuated osteoblast differentiation and mineralization. 48 In another study, suppression of KLF4 in hMSCs enhanced both osteogenic and adipogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Biomineralized Matrices Dominate Soluble Cues To Direct Osteogenic Differentiation of Human Mesenchymal Stem Cells through Adenosine Signaling

2015

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Stem cell differentiation is determined by a repertoire of signals from its microenvironment, which includes the extracellular matrix (ECM) and soluble cues. The ability of mesenchymal stem cells (MSCs), a common precursor for the skeletal system, to differentiate into osteoblasts and adipocytes in response to their local cues plays an important role in skeletal tissue regeneration and homeostasis. In this study, we investigated whether a bone-specific calcium phosphate (CaP) mineral environment could induce osteogenic differentiation of human MSCs, while inhibiting their adipogenic differentiation, in the presence of adipogenic-inducing medium. We also examined the mechanism through which the mineralized matrix suppresses adipogenesis of hMSCs to promote their osteogenic differentiation. Our results show that hMSCs cultured on mineralized matrices underwent osteogenic differentiation despite being cultured in the presence of adipogenic medium, which indicates the dominance of matrix-based cues of the mineralized matrix in directing osteogenic commitment of stem cells. Furthermore, the mineralized matrix-driven attenuation of adipogenesis was reversed with the inhibition of A2b adenosine receptor (A2bR), implicating a role of adenosine signaling in mineralized environment-mediated inhibition of adipogenesis. Such synthetic matrices with an intrinsic ability to direct differentiation of multipotent adult stem cells toward a targeted phenotype while inhibiting their differentiation into other lineages not only will be a powerful tool in delineating the role of complex microenvironmental cues on stem cell commitment but also will contribute to functional tissue engineering and their translational applications.

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“…While the A2bAR affects glucose disposal, it also affects other aspects of whole body energy homeostasis. For one, the A2bAR plays a role in regulating adipogenesis (Eisenstein et al, ). Activation of the receptor with BAY 60‐6583 inhibits adipogenesis (Eisenstein et al, ).…”

Section: Inflammatory Processes Underlying Cardiovascular and Metabolmentioning

confidence: 99%

“…For one, the A2bAR plays a role in regulating adipogenesis (Eisenstein et al, ). Activation of the receptor with BAY 60‐6583 inhibits adipogenesis (Eisenstein et al, ). Furthermore, the A2bAR regulates insulin secretion from pancreatic β‐cells (Rusing et al, ; Johnston‐Cox et al, ).…”

Section: Inflammatory Processes Underlying Cardiovascular and Metabolmentioning

confidence: 99%

The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases

Eisenstein

Patterson

Ravid

2015

Journal Cellular Physiology

Self Cite

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Modulation of the low affinity adenosine receptor subtype, the A2b adenosine receptor (A2bAR), has gained interest as a therapeutic target in various pathologic areas associated with cardiovascular disease. The actions of the A2bAR are diverse and at times conflicting depending on cell and tissue type and the timing of activation or inhibition of the receptor. The A2bAR is a promising and exciting pharmacologic target, however, a thorough understanding of A2bAR action is necessary to reach the therapeutic potential of this receptor. This review will focus on the role of the A2bAR in various cardiovascular and metabolic pathologies in which the receptor is currently being studied. We will illustrate the complexities of A2bAR signaling and highlight areas of research with potential for therapeutic development.

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An Adenosine Receptor-Krüppel-like Factor 4 Protein Axis Inhibits Adipogenesis

Cited by 32 publications

References 71 publications

Transcriptional Networks in Single Perivascular Cells Sorted from Human Adipose Tissue Reveal a Hierarchy of Mesenchymal Stem Cells

Transcriptional Networks in Single Perivascular Cells Sorted from Human Adipose Tissue Reveal a Hierarchy of Mesenchymal Stem Cells

Biomineralized Matrices Dominate Soluble Cues To Direct Osteogenic Differentiation of Human Mesenchymal Stem Cells through Adenosine Signaling

The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases

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