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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 11, 2021 |
| Title |
Aged skeletal stem cells during fracture healing |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Skeletal aging and disease are associated with a misbalance in the opposing actions of osteoblasts and osteoclasts that are responsible for maintaining the integrity of bone tissues. Here, we show through detailed functional and single-cell genomic studies that intrinsic aging of bona fide mouse skeletal stem cells (SSCs) alters bone marrow niche signaling and skews bone and blood lineage differentiation leading to fragile bones that regenerate poorly. Aged SSCs have diminished bone and cartilage forming potential but produce higher frequencies of stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell transcriptomic studies reveal a distinct population of SSCs in aged mice that gradually outcompete their younger counterparts in the bone marrow niche. While systemic exposure to a youthful circulation through heterochronic parabiosis reduced local expression of inflammatory cytokines, it did not reverse the diminished osteochondrogenic activity of aged SSCs and was insufficient to improve bone mass and skeletal-healing parameters in aged mice. Hematopoietic reconstitution of aged mice with young hematopoietic stem cells (HSC) also did not improve bone integrity and repair. We find that deficient bone regeneration in aged mice could only be reversed by the local application of a combinatorial treatment that re-activates aged SSCs and simultaneously abates crosstalk to hematopoietic cells favoring an inflammatory milieu. This treatment expanded aged SSC pools, reduced osteoclast activity, and enhanced bone healing to youthful levels. Our findings provide mechanistic insight into the complex, multifactorial mechanisms underlying skeletal aging and offer new prospects for rejuvenating the aged skeletal system.
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| Overall design |
Bulk RNA-sequencing gene expression profiling of mSSCs from fracture callus tissue of adult (2-months), middle-aged (12 months), and aged (24-months) mice at ten days post injury.
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| Contributor(s) |
Ambrosi TH, Marecic O, McArdle A, Sinha R, Gulati GS, Tong X, Wang Y, Steininger H, Hoover MY, Koepke LS, Murphy MP, Sokol J, Seo E, Tevlin R, Lopez M, Conley SD, Brewer RE, Mascharak S, Lu L, Ajanaku O, Morri M, Seita J, Neff N, Sahoo D, Yang F, Weissman IL, Longaker MT, Chan CK |
| Citation(s) |
34381212 |
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| Submission date |
Feb 09, 2021 |
| Last update date |
Sep 10, 2021 |
| Contact name |
Thomas H Ambrosi |
| E-mail(s) |
[email protected]
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| Phone |
9162983241
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| Organization name |
UC Davis
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| Street address |
2700 Stockton Blvd
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| City |
Sacramento |
| State/province |
California |
| ZIP/Postal code |
95817 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA700970 |
| SRA |
SRP305495 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE166441_AgingFractureSSC_Log2_TPM_norm_Table.xlsx |
4.7 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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