Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration
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De novo limb regeneration after amputation is restricted in mammals to the distal digit tip. Central to this regenerative process is the blastema, a heterogeneous population of lineage-restricted, dedifferentiated cells that ultimately orchestrates regeneration of the amputated bone and surrounding soft tissue. To investigate skeletal regeneration, we made use of spatial transcriptomics to characterize the transcriptional profile specifically within the blastema. Using this technique, we generated a gene signature with high specificity for the blastema in both our spatial data, as well as other previously published single-cell RNA-sequencing transcriptomic studies. To elucidate potential mechanisms distinguishing regenerative from non-regenerative healing, we applied spatial transcriptomics to an aging model. Consistent with other forms of repair, our digit amputation mouse model showed a significant impairment in regeneration in aged mice. Contrasting young and aged mice, spatial analysis revealed a metabolic shift in aged blastema associated with an increased bioenergetic requirement. This enhanced metabolic turnover was associated with increased hypoxia and angiogenic signaling, leading to excessive vascularization and altered regenerated bone architecture in aged mice. Administration of the metabolite oxaloacetate decreased the oxygen consumption rate of the aged blastema and increased WNT signaling, leading to enhanced in vivo bone regeneration. Thus, targeting cell metabolism may be a promising strategy to mitigate aging-induced declines in tissue regeneration.
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Visium has been used to investigate the spatial characteristics of cellular senescence in mouse and human brains and to decipher age-dependent tissue-regeneration capabilities.
“Already there are reports of Visium being used to investigate the spatial characteristics of cellular senescence in mouse52 and human brains53 as well as to decipher age-dependent tissue-regeneration capabilities54.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [54]
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Advances in Spatial Transcriptomics in Bone
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SpatialFlux: an R package for distance gradient analysis in spatial transcriptomics
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Self-citation
- Authors
- Tower, R. J., Busse, E., Jaramillo, J., Lacey, M., Hoffseth, K., Guntur, A. R., Simkin, J., & Sammarco, M. C.
- Affiliations
- Johns Hopkins University (US)
- Tulane University (US)
- Louisiana State University (US)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Tower, Robert J
- Sammarco, Mimi C
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-05-26
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9135401
- OpenAlex
- W4281723078
- Cited by
- 43
- References
- 76
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 13 · 2023: 10 · 2022: 1
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (P20GM103629)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- digit regeneration, blastema, aging, skeletal regeneration, cellular metabolism, hypoxia, angiogenesis, bone regeneration, oxaloacetate, Wnt signaling, oxygen consumption, gene expression signatures, amputation
- MeSH terms
- Amputation, Surgical, Animals, Bone and Bones, Bone Regeneration, Extremities, Mammals, Wound Healing, Mice, Transcriptome
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