Understanding the Role of the Immune System in Improving Tissue Regeneration Proceedings of a Workshop (2022) / Chapter Skim
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5 Endogenous Regeneration and the Role of the Local Environment in Repair
5 Endogenous Regeneration and the Role of the Local Environment in Repair
Pages 53-72
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From page 53... ...
Depending on its location, DEL-1 can regulate neutrophil recruitment, promote in flammation resolution, or induce bone regeneration. (Hajishengallis)
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From page 54... ...
Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology at Stanford University, discussed the discovery that prostaglandin E2 (PGE2) , an inflammatory metabolite, is crucial to muscle regeneration.
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From page 55... ...
. Andrew Ho and Adelaida Palla, scientists from the Baxter Laboratory for Stem Cell Biology at Stanford University, conducted a bioinformatic analysis of the transcriptome of activated stem cells acutely post-injury (Ho et al., 2017)
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From page 56... ...
. Therefore, this pathway is extremely important for enabling stem cells to proliferate, expand, and repair the damage, and young mice became weaker after injury due to their inability to repair muscle damage, Blau explained.
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From page 57... ...
To test whether targeting the degradation enzyme, 15-PGDH, would increase PGE2 levels, researchers used a small molecule inhibitor, SW033291, and administered daily intraperitoneal injections of the inhibitor to aged mice for one month, Blau explained. This resulted in the degrading enzyme, 15-PGDH, decreasing by approximately 30 percent and a consequent twofold increase in PGE2 and PGD2, constituting a return to youthful levels (Palla et al., 2021)
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From page 58... ...
Aged mouse muscle tissue featured distended, vacuous, dysfunctional mitochondria. After aged mice received one month of treatment, muscle tissue was remodeled to a youthful structure with intact myofibrils and condensed mitochondria in orderly pairs, described Blau.
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BIOMATERIALS FOR MODELING IMMUNE MEDIATION IN WOUND HEALING Erika Moore, Rhines Rising Star Larry Hench Assistant Professor at the University of Florida Department of Materials Science and Engineering, discussed the use of biomaterials for modeling immune cell mediation in wound healing. The inherent variability observed in wound healing creates an opportunity to use biomaterials to mimic differences in wound-healing environments.
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From page 60... ...
Through these two types of biomaterials, the wound-healing process could be manipulated in order to assess the B-cell response in each of these environments, explained Moore. Researchers induced muscle injury in mice, implanted biomaterial directly into the wound, and interrogated the injury sites.
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From page 61... ...
Moore highlighted a dichotomy in the roles that B cells can play depending on their antigen-mature state, the maturity of the B cells, and on the timing of their recruitment to the injury site. Moore and her colleagues investigate wound healing with the goal of achieving clinical relevance.
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From page 62... ...
Additionally, researchers do not know whether the B-cell role either in local tissue response or in secreting antibodies informs the systemic response. Moore remarked on her interest in understanding how to connect the local injury response to systemic immunity by linking the B-cell responses at the local and systemic response sites.
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From page 63... ...
. DEL-1 is expressed primarily by tissue-resident cells, including endothelial cells, neuronal cells, and mesenchymal stem cells (MSC)
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From page 64... ...
When DEL-1 is expressed by endothelial cells, its job is to regulate neutrophil recruitment. However, when DEL-1 is produced by macrophages, the protein promotes efferocytosis and inflammation resolution because it can serve as a molecular bridge to facilitate the interaction of apoptotic neutrophils with macrophages (Kourtzelis et al., 2019)
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From page 65... ...
Given that DEL-1 is expressed in the MSC niche of the periodontal ligament, they believe that the aging-related DEL-1 deficiency contributes to stem cell niche dysfunction in the periodontal ligament, he explained. This in turn may contribute to
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From page 66... ...
The cell type by which DEL-1 mediates bone regeneration is unknown, although the MSCs in the periodontal ligament are likely responsible because they express DEL-1, he acknowledged. Should this be proven, it would signify that DEL-1 expressed in the MSC niche promotes differentiation of MSCs into osteoblast progenitors that then become osteoblasts.
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From page 67... ...
Given that the local environment affects stem cells, Becker asked how components of the environments can be manipulated to support tissue regeneration. Blau answered that more study is needed on how the niche is affected, what the components of the niches are, and how they change through perturbations.
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From page 68... ...
For instance, the pro-healing material she has studied delivers extracellular matrix that has been stripped of cells to stimulate a type 2 immune response at the wound site. Researchers are working to understand whether that can be leveraged to promote healing in older individuals by manipulating the endogenous injury site to recreate the injury microenvironments present in a younger person, she elaborated.
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From page 69... ...
. Beyond profiling individual cell types, understanding the intracellular communications between different types of immune cells that are recruited to these sites is an area of interest.
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. Moore replied that her lab profiled the peritoneum and the spleen to study the systemic response after a muscle injury.
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From page 71... ...
Moore added that MSCs are particularly immunomodulatory and immune sensitive, and that manipulating the carriers used for MSC injection -- perhaps by injecting them in a hydrogel mesh -- might promote immune cell recruitment. Opportunities to marry the fields of endogenous immune modulation and exogenous cell replacement therapy include shifting the immunological response to cell therapies and could leverage the benefits of both, Moore suggested.
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