Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration.
aging
bone regeneration
cell biology
cell metabolism
digit regeneration
mouse
oxaloacetate
spatial transcriptomics
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
26 05 2022
26 05 2022
Historique:
received:
22
06
2021
accepted:
18
05
2022
entrez:
26
5
2022
pubmed:
27
5
2022
medline:
31
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35616636
doi: 10.7554/eLife.71542
pii: 71542
pmc: PMC9135401
doi:
pii:
Banques de données
GEO
['GSE180682', 'GSE135985', 'GSE143888']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103629
Pays : United States
Informations de copyright
© 2022, Tower et al.
Déclaration de conflit d'intérêts
RT, EB, JJ, ML, KH, AG, JS, MS No competing interests declared
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