Elsevier

Journal of Surgical Research

Volume 245, January 2020, Pages 1-12
Journal of Surgical Research

Vascular
Activation of Bone Marrow–Derived Cells and Resident Aortic Cells During Aortic Injury

https://doi.org/10.1016/j.jss.2019.07.013Get rights and content

Abstract

Background

The process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection.

Materials and methods

Wild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP− resident aortic cells.

Results

Aortic challenge induced recruitment of GFP+ BM cells and activation of GFP− resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non−BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells.

Conclusions

BM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Introduction

Aortic aneurysm and dissection (AAD) are major diseases of the aorta, accounting for more than 10,000 deaths in the United States each year.1 Despite improvements in diagnostic and therapeutic techniques, patients with AAD have a high mortality rate. Understanding the mechanisms of AAD formation is important for developing new treatment options.

The aortic wall is constantly subjected to biologic insults and hemodynamic stress, which can cause aortic inflammation, smooth muscle cell (SMC) damage,2 and extracellular matrix destruction.3 When the aorta is injured, complex interconnected programs may be triggered to quickly restore tissue homeostasis,4 such as the recruitment of inflammatory cells to the injured area to clear damaged tissue,5, 6 the activation and differentiation of stem cells to replace the damaged cells, the proliferation of SMCs to replace the lost cells, and the rapid proliferation of fibroblasts that produce collagen to strengthen the aortic wall and prevent rupture.7, 8, 9 However, the reparative process that occurs in response to aortic injury is poorly understood.

Bone marrow (BM)-derived cells have been shown to directly participate in vascular repair and regeneration10, 11, 12 by producing growth factors.13 To understand the reparative process after AAD and to determine the relative contributions of BM-derived versus resident aortic cells in aortic repair and remodeling, we systematically examined the recruitment, activation, differentiation potential, and growth factor production of BM-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic AAD.

Section snippets

Experimental design and model of sporadic AAD

All animal procedures were approved by the Institutional Animal Care and Use Committee at Baylor College of Medicine in accordance with the guidelines of the National Institutes of Health. Eight-week-old male wild-type C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) (n = 28) were lethally irradiated and then subjected to BM transplantation as described in the following section. Four weeks after transplantation, the mice were either challenged with a high-fat diet and continuous angiotensin II

Reconstitution of BM in irradiated wild-type recipient mice

To facilitate the tracking of BM-derived cells, recipient mice were transplanted with BM cells from GFP+ mice. FACS analysis of the donor BM cells showed the absence of FSP-1+ fibroblasts and CD68+ macrophages (data not shown). Four weeks after transplantation, FACS analysis of the peripheral blood from the 28 mice showed that 97.1%-99.0% of all nucleated cells expressed GFP, indicating near complete reconstitution of BM in the recipient mice (online-only Supplemental Fig). Furthermore, the

Discussion

In this study, we showed that both BM-derived and resident aortic cells were activated in response to aortic stress, produced growth factors, and formed fibroblasts and inflammatory cells. Resident stem/progenitor cells were more prominent than BM-derived stem/progenitor cells in the aortas of challenged mice. Our findings suggest that BM-derived and resident stem/progenitor cells are activated in response to aortic stress and may contribute to aortic repair and remodeling by developing into

Conclusions

In summary, we found using an experimental model of AAD that BM-derived and resident aortic cells are activated in response to aortic stress. BM-derived cells and aortic resident cells contribute equally to aortic inflammatory cells and fibroblasts. Resident aortic cells contribute to the majority of progenitors. Our findings suggest that BM-derived cells and aortic resident cells play differential and dynamic roles in aortic inflammation, repair, and remodeling.

Acknowledgment

This study was supported by the National Institutes of Health [grant R01 HL085341 (to S.A.L.). S.A.L.'s work is supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. S.Z. was supported by a program from SHMEC (15ZZ042) and a program from NSFC (81700408). The authors thank Darren Woodside, PhD, and Deenadayalan Bakthavatsalam, PhD (Texas Heart Institute), for their expert advice regarding use of the confocal microscope. The

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