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Macrophages adopt mural cell function and marker expression following ischemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In response to tissue ischemia, angiogenesis is initiated and macrophages accumulate in perivascular positions. Mural cells (pericytes and smooth muscle cells) will in this process also attain a perivascular position and mediate blood vessel maturation and blood flow regulation. With fate mapping of macrophages following hindlimb ischemia in mouse models, we show that ischemia-recruited perivascular macrophages down-regulate the expression of the myeloid cell lineage markers CD45, CX3CR1, and CD11b and upregulate expression of the mural cell markers PDGFRβ. Depletion of macrophages in the context of ischemia resulted in severe mural cell deficiency in newly formed vessels and impaired blood vessel maturation.  Taken together, we here demonstrate that macrophages are crucial for blood vessel maturation following ischemic injury by adopting a mural cell identity. 

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-395533OAI: oai:DiVA.org:uu-395533DiVA, id: diva2:1362485
Note

* Indicates equal contribution

Available from: 2019-10-20 Created: 2019-10-20 Last updated: 2019-10-21
In thesis
1. On macrophage contributions to tissue homeostasis: New insights on pancreas development and healing of ischemic injury
Open this publication in new window or tab >>On macrophage contributions to tissue homeostasis: New insights on pancreas development and healing of ischemic injury
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Besides providing host defence against innumerable threats, macrophages display additional key functions for preservation of tissue homeostasis. This thesis includes four studies that explore novel macrophage functions in both the development of islets of Langerhans and healing of ischemic injury in mice.

The aim of Study I was to explore the involvement of pancreatic macrophages in postnatal islet development. We found that neonatal pancreas contained high density of macrophages. Neonatal infections reduced the number of pancreatic macrophages transiently and resulted in both impaired β cell maturation and associated long-standing glucose intolerance. Moreover, clodronate depletion of pancreatic macrophages in the neonate also resulted in long-standing impairment of glucose handling. Together, these results demonstrate that macrophages in the neonatal pancreas are important for maturation of islet function.

We then wanted to understand how macrophages contribute to healing of ischemic injury based on the observation that they accumulate at perivascular positions following ischemia. We found that blood flow at the site of ischemia was regulated by perivascular macrophages in an iNOS-dependent manner, which could be targeted to increase tissue healing (Study II). Next, we investigated if these perivascular macrophages trans-differentiate into mural cells. By lineage tracing, we found that macrophages undergo a phenotype shift at the site of ischemic injury, as they down-regulated the expression of myeloid cell lineage markers (CD45/CX3CR1/CD11b) and upregulated the expression of the mural cell marker PDGFRβ (Study III). Lastly, we addressed if macrophages are involved in vascular remodelling important for tissue normalization by pruning excessive vessels at the site of injury. Indeed, MMR+-macrophages were found to support vessel pruning during vascular normalization at late phases of healing (Study IV).

In conclusion, this thesis reveals novel functions of macrophages as they support postnatal maturation of the insulin-producing β cells of the pancreas, as well as restore blood flow and normalize the vasculature during healing of ischemic injuries. Together, the studies in this thesis contribute to illustrating the ample and diverse macrophage curriculum and how macrophage skills cooperate to ensure homeostasis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 82
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1605
Keywords
macrophages, islets of Langerhans, β cell function, postnatal β cell maturation, hindlimb ischemia, blood flow regulation, mural cells, vessel pruning, diabetes mellitus, ischemic diseases
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-395535 (URN)978-91-513-0787-9 (ISBN)
Public defence
2019-12-06, Room B41, BMC, Hursagatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-11-15 Created: 2019-10-21 Last updated: 2019-11-15

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