Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization During Bone Repair

Selma, Jada; Das, Ashim; Awojoodu, Anthony O.; Wang, Tiffany; Kaushik, Anjan P.; Cui, Quanjun; Song, Hannah; Ogle, Molly E.; Olingy, Claire; Pendleton, Emily G.; Tehrani, Kayvan Forouhesh; Mortensen, Luke J.; Botchwey, Edward A.

doi:10.1007/s12195-018-0532-0

Cited by 8 publications

(5 citation statements)

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“…SLs are a highly diverse family of molecules which are important building blocks of eukaryotic membranes 33 . Prior to this work, we demonstrated that modulating novel sphingosine-1-phosphate (S1P) and S1P receptor 3 (S1PR3) signaling mobilizes both hematopoietic stem cells (HSCs) and MSCs to enhance ectopic bone growth, further emphasizing the importance of understanding SL functions 46,47 . In this study, we performed LC-MS/MS to characterize AD-, BM-, and UCT-MSCs sphingolipid metabolism profiles.…”

Section: Discussionmentioning

confidence: 99%

Characterizing human mesenchymal stromal cells’ immune-modulatory potency using targeted lipidomic profiling of sphingolipids

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Characterizing human mesenchymal stromal cells’ immune-modulatory potency using targeted lipidomic profiling of sphingolipids

et al. 2022

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“…Complementary to our results, previous studies have shown that S1PR3 overexpression alone is sufficient to induce myeloid differentiation in human HSC 38 . In addition, S1PR3 has been implicated in the mobilization from the bone marrow to the peripheral blood of hematopoietic and mesenchymal progenitors 39,40 . The decreased efficiency of in vitro monocyte maturation, and relative increase in the fraction of bone marrow CD14 + monocytes with reciprocal decrease of bone marrow CD16 + neutrophils of engrafted mice, may suggest that S1PR3 both plays cell autonomous roles in monocytes during maturation as well as impacts the trafficking of myeloid cells from bone marrow stores to circulating cells in the peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…Supporting this hypothesis, S1P receptors, which are chemotactically sensitive to S1P gradients, regulate multiple processes, including migration, matrix adhesion, and cell-cell contact. Therefore, the steep gradient of S1P concentration existing between bone marrow and blood might promote monocytes to navigate from the bone marrow to circulation 40 . The biological contributions of S1PR3 to monocyte maturation and trafficking may be complex and could merit future dedicated study.…”

Section: Discussionmentioning

confidence: 99%

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Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program

et al. 2022

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Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

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“…Supporting this hypothesis, S1P receptors, which are chemotactically sensitive to S1P gradients, regulate multiple processes, including migration, matrix adhesion, and cell-cell contact. Therefore, the steep gradient of S1P concentration existing between bone marrow and blood, may drive cell types including monocytes, to navigate from the bone marrow to circulation 40 .…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program

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Stilp

Rao

et al. 2021

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Genome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

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Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization During Bone Repair

Abstract: Our studies suggest that MSC mobilization through S1PR3 antagonism is a promising strategy for endogenous tissue engineering and improving MSC delivery to treat bone diseases.

Cited by 8 publications

References 70 publications

Characterizing human mesenchymal stromal cells’ immune-modulatory potency using targeted lipidomic profiling of sphingolipids

Characterizing human mesenchymal stromal cells’ immune-modulatory potency using targeted lipidomic profiling of sphingolipids

Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program

Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program

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