Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/71542 |
| _version_ | 1797998093791133696 |
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| author | Robert J Tower Emily Busse Josue Jaramillo Michelle Lacey Kevin Hoffseth Anyonya R Guntur Jennifer Simkin Mimi C Sammarco |
| author_facet | Robert J Tower Emily Busse Josue Jaramillo Michelle Lacey Kevin Hoffseth Anyonya R Guntur Jennifer Simkin Mimi C Sammarco |
| author_sort | Robert J Tower |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:43:03Z |
| format | Article |
| id | doaj.art-2a598576685044ffb8c6917409c773c1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:43:03Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2a598576685044ffb8c6917409c773c12022-12-22T04:29:08ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.71542Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regenerationRobert J Tower0https://orcid.org/0000-0001-5856-5758Emily Busse1Josue Jaramillo2Michelle Lacey3Kevin Hoffseth4Anyonya R Guntur5Jennifer Simkin6Mimi C Sammarco7https://orcid.org/0000-0001-9491-5735Department of Orthopaedics, Johns Hopkins University, Baltimore, United StatesDepartment of Surgery, Tulane School of Medicine, New Orleans, United StatesDepartment of Surgery, Tulane School of Medicine, New Orleans, United StatesDepartment of Mathematics, Tulane University, New Orleans, United StatesDepartment of Biological & Agricultural Engineering, Louisiana State University, Baton Rouge, United StatesCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United StatesDepartment of Orthopaedic Surgery, Louisiana State University Health Sciences Center, New Orleans, United StatesDepartment of Surgery, Tulane School of Medicine, New Orleans, United StatesDe 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.https://elifesciences.org/articles/71542digit regenerationagingcell metabolismbone regenerationspatial transcriptomicsoxaloacetate |
| spellingShingle | Robert J Tower Emily Busse Josue Jaramillo Michelle Lacey Kevin Hoffseth Anyonya R Guntur Jennifer Simkin Mimi C Sammarco Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration eLife digit regeneration aging cell metabolism bone regeneration spatial transcriptomics oxaloacetate |
| title | Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration |
| title_full | Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration |
| title_fullStr | Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration |
| title_full_unstemmed | Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration |
| title_short | Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration |
| title_sort | spatial transcriptomics reveals metabolic changes underly age dependent declines in digit regeneration |
| topic | digit regeneration aging cell metabolism bone regeneration spatial transcriptomics oxaloacetate |
| url | https://elifesciences.org/articles/71542 |
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