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Age-related Remodeling is Associated with Altered Cardiac Resident and Circulation-derived Macrophage Phenotype and Function

Haschak, Martin (2022) Age-related Remodeling is Associated with Altered Cardiac Resident and Circulation-derived Macrophage Phenotype and Function. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Increased age is associated with an increased risk of cardiovascular disease incidence. This increased risk can be attributed to several processes which occur with increasing age - including an accumulation of intracellular damage, altered resident cell metabolism, increased secretion of cytokines characteristic of the senescence-associated cell phenotype, and altered deposition of matrix proteins within the extracellular microenvironment. Considering the limited regenerative therapeutic availability for heart failure patients coupled with the limited availability of donor organs, understanding the mechanisms by which these processes induce altered cardiac cell function will be important to attenuate the cardiovascular disease risk which faces the aging United States population. Cardiac resident macrophages have been identified as both essential mediators of cardiac homeostasis as well as important regulators of the cardiac tissue remodeling response. Given the numerous changes which occur in the aging cardiac microenvironment coupled with the importance of microenvironmental stimuli in inducing macrophage phenotype, in vitro and in vivo models of differing cardiac microenvironments were developed to better understand the consequences of this remodeling on cardiac macrophage phenotype and function. Significant alterations in macrophage morphology and function were observed in response to the differing in vitro culture conditions, with substrates of increased stiffness promoting increasingly inflammatory functional responses. Additionally, macrophage culture with decellularized cardiac extracellular matrix isolated from aged individuals was found to attenuate macrophage functional capacity. An in vivo model of cardiac microenvironmental remodeling was then developed and flow cytometry was utilized to characterize any changes in cardiac resident macrophage regulation. The developed in vivo model was found to recapitulate several hallmark cardiac tissue remodeling features observed in aged individuals, including cardiomyocyte hypertrophy and increased perivascular fibrosis. These microenvironmental alterations were found to promote CX3CR1+ macrophage subset expansion and increased pro-inflammatory CD86 expression in all characterized subsets. Cardiac microenvironmental remodeling was also found to induce increased expression of pro-inflammatory, pro-fibrotic, and stress response-associated genes. Murine echocardiographic assessment also suggested some impaired ventricular relaxation resultant of the experimentally induced cardiac remodeling. These models help elucidate the impact that age-related cardiac microenvironmental biochemical and biomechanical change plays in promoting altered macrophage phenotype and function.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrown,
Committee MemberBorovetz,
Committee MemberShroff,
Committee MemberYates,
Date: 16 January 2022
Date Type: Publication
Defense Date: 13 September 2021
Approval Date: 16 January 2022
Submission Date: 4 November 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 299
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Macrophage, microenvironment, cardiac
Date Deposited: 16 Jan 2022 14:46
Last Modified: 16 Jan 2022 14:46


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