Mesenchymal stromal cells in wound healing
Abstract/Contents
- Abstract
- Abnormal wound healing is a significant healthcare problem with rising at-risk patient populations. Despite the multitude of treatment modalities available, few therapies can reverse the deficiencies that contribute to delayed or non-healing wounds. Mesenchymal stromal cells (MSCs) have emerged as a promising next-generation therapy for wound repair due to their ability to secrete trophic factors that modulate inflammation and promote regeneration. This work first provides a comprehensive overview of the intricate process of wound healing and the individual roles of resident cell types to identify potential points of therapeutic intervention at each stage of the wound healing cascade. Secondly, using lineage tracing, multiple models of ischemic injury, and single cell transcriptional analysis, we identify a population of non-hematopoietic, non-endothelial circulating progenitor cells that homes to regions of ischemia and may contribute to tissue repair. We demonstrate that these cells engraft adjacent to endothelial cells, display mesenchymal morphology, and deposit extracellular matrix, suggesting that they may be the in vivo equivalent of MSCs cultured in vitro. Thirdly, we explore the fate of mesenchymal stromal cells following intravenous infusion and their impact on wound healing. Using a mouse excisional wound healing model, we demonstrate that infusion of MSCs leads to pulmonary entrapment followed by rapid clearance from the recipient, but also significantly accelerates wound closure. Using single cell RNA-sequencing of the wound, we show that following MSC delivery, innate immune cells, particularly macrophages, exhibit distinctive transcriptional changes. We identify the appearance of a pro-angiogenic CD9+ macrophage subpopulation, whose induction is mediated by several proteins secreted by MSCs, including COL6A1, PRG4, and TGFB3. These findings suggest that MSCs do not need to act locally to induce broad changes in the immune system and ultimately treat disease. Finally, we investigate the age-related impacts on cellular function of MSCs. We demonstrate that delivery of MSCs from young donors resulted in significantly faster healing compared to delivery of MSCs from older donors. Using single-cell transcriptomic analysis to provide potential molecular insights into these observations, we demonstrate that cells from young donors contain a higher proportion of cells characterized by a higher expression of genes involved in tissue regeneration. In addition, we identify a unique, quiescent subpopulation that is exclusively present in young donor cells. These findings may explain a novel mechanism for the enhanced healing capacity of young stem cells and may have implications for autologous cell therapy in the extremes of age.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Kosaric, Nina |
|---|---|
| Degree supervisor | Gurtner, Geoffrey |
| Thesis advisor | Gurtner, Geoffrey |
| Thesis advisor | Longaker, Michael T |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Degree committee member | Longaker, Michael T |
| Degree committee member | Majeti, Ravindra, 1972- |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Nina Kosaric. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Nina Kosaric
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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