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6 Modulating the Host Immune System to Create a Pro-Regenerative Environment
Pages 73-94

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From page 73...
... (Kirkland) • Regenerative immunology marries the fields of regenerative medi cine, immunology, and biomaterial design to develop novel engineered therapies to promote endogenous tissue regeneration.
From page 74...
... The session was moderated by Candace Kerr, program officer of the Stem Cell Program of the Aging Physiology Branch at the National Institute on Aging. CELLULAR SENESCENCE, SENOLYTICS, AND ORGAN REGENERATION AND TRANSPLANTATION James Kirkland, director of the Robert and Arlene Kogod Center on Aging and Noaber Foundation Professor of Aging Research at the Mayo Clinic, discussed fundamental aging processes and their effects on issues related to organ regeneration and transplantation.
From page 75...
... Furthermore, acutely generated senescent cells defend against cancer development and infection and support wound healing and tissue remodeling. Even in seemingly unrelated processes like parturition, senescent cells accumulate in the placenta and produce factors that drive the neonate through the birth canal.
From page 76...
... Mice with transplanted senescent cells tend to die prematurely due to all typical age-related diseases, not any specific disease, Kirkland highlighted. These findings support a causal link between senescent cells and multimorbidity, since adding a small number of senescent cells can accelerate age-related health problems and death from all causes (Xu et al., 2018)
From page 77...
... Furthermore, the 30–70 percent of senescent cells that have a pro-apoptotic, tissue-damaging SASP can secrete noncoding nucleotides, including mitochondrial DNA. Iske and colleagues showed that mitochondrial DNA produced by senescent cells in the hearts from the old mice activates dendritic cells in draining lymph nodes and substantially accelerates graft-versus-host disease (Iske et al., 2020)
From page 78...
... . Since dasatinib did not kill senescent HUVECs and quercetin did not kill senescent pre-adipocytes, a combination of the two agents was investigated in mice and was able to eliminate a broader range of senescent cell types than either agent could alone (Zhu et al., 2015)
From page 79...
... These two fields and their limitations led to the development of tissue engineering, which aims to provide new healthy tissue by taking a biomaterial scaffold that serves as a three-dimensional framework for components like stem cells and where specified biological signals can promote tissue development. Unfortunately, clinical translation of tissue engineering discoveries has been slow, Elisseeff remarked.
From page 80...
... Although cells such as macrophages have long been recognized for their role in tissue repair, cells of the adaptive immune system, such as T cells, had not previously been considered as having a critical role. To inform efforts to engineer immunotherapies, Elisseeff and colleagues began mapping these immune responses and investigating how they influence downstream processes such as vascularization, tissue development, and mobilization of different immune cell types.
From page 81...
... FIGURE 6-1  Foundations of regenerative immunology. SOURCE: Elisseeff presentation, November 3, 2021.
From page 82...
... . The dichotomy of these biomaterial-specific immune responses can be thought of as a balance, Elisseeff described.
From page 83...
... Clearing senescent cells after injury can promote tissue repair simply by removing inhibitory factors without requiring additional growth factors or stem cells. However, senescent cells are immunologically active and impact multiple immune cell types, she noted.
From page 84...
... Efforts are ongoing to map the immune–stromal response (i.e., the immune response and the range of interconnected cell types that lead to immune changes and regulate tissue repair)
From page 85...
... Therefore, leveraging tools of cancer immunology could inform work on wound healing, and wound healing studies can broaden understanding of tumors, she elaborated. RESOLUTION OF ACUTE INFLAMMATION STIMULATES TISSUE REGENERATION Charles Serhan, endowed distinguished scientist and director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham Women's Hospital and professor of anesthesia at Harvard Medical School, presented evidence that resolving inflammation can stimulate tissue regeneration via novel specialized pro-resolving mediators (SPM)
From page 86...
... SOURCE: Serhan presentation, November 3, 2021. means of pinpointing where and when the pro-resolving lipid mediators act, he added.
From page 87...
... . Promising research has shown that SPMs can stimulate stem cells, including periodontal stem cells, neural stem cells, mesenchymal stem cells, and muscle stem cells (Cianci et al., 2016; Dort et al., 2021)
From page 88...
... Moreover, they stimulate tissue regeneration, as demonstrated in the planaria study. These data suggest the potential for these pro-resolving mediators in regenerative therapies, he added.
From page 89...
... Elisseeff added that stem cells can proliferate or they can differentiate. She posited that senescent cells could be considered simply as a differentiation state in a signaling cell.
From page 90...
... The Senescence Profile and Immunologically Induced Senescence Kirkland was asked about the long-term effects of the senescence profile on the extracellular matrix, the associated immunological effects, and whether senolytic agents could reverse tissue-level changes. The SASP is complex, varies across different senescent cell types, and evolves over time depending upon the nature of the induced senescence, he explained.
From page 91...
... She and her colleagues are looking at senescent cell–inducing IL-17 production by various cell types. They have also observed IL-17–producing cells and IL-17– inducing cells that were fibroblasts that were previously healthy, which they refer to as an immunologically induced senescence.
From page 92...
... The receptors are present on various stem cells, but after the receptor–ligand interaction, the cellular mechanisms of action are highly cell-type-dependent. Kerr inquired about the effects of immune response manipulation on stem progenitor cells.
From page 93...
... There are potential benefits of manipulating immune responses as well as dangers, she said. Serhan added that evidence is emerging about the effects of resolvins on autoimmunity for osteoarthritis and rheumatoid arthritis, for example, in which the administration of resolvins appears to result in a diminished inflammatory response and improved cartilage production and function.


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