Stem cells in thoracic aortic aneurysms and dissections: potential contributors to aortic repair

Abstract

Background: The hallmark of thoracic aortic aneurysms and dissections (TAAD) is progressive medial degeneration, which can result from excessive tissue destruction and insufficient repair. Although multipotent stem cells (SCs) are important in tissue repair, their role in TAAD is unknown. We sought to determine whether SCs are more abundant in TAAD tissue than in control tissues, and whether SCs within the diseased aortic wall differentiate into functionally relevant cell types.

Methods: Using immunohistochemistry, we compared the abundance of STRO-1+ cells, c-kit+ cells, and CD34+ cells in aortic tissue from patients with descending thoracic aortic aneurysms (n=12), patients with chronic descending thoracic aortic dissections (n=18), and age-matched organ donors (n=5). Using double immunofluorescence staining, we evaluated SC differentiation into smooth muscle cells, fibroblasts, and macrophages.

Results: All three cell types were significantly more abundant in the media and adventitia of TAAD tissues than in control tissues. We identified subsets of STRO-1+ cells, c-kit+ cells, and CD34+ cells that also expressed the smooth muscle cell marker SM22-α or fibroblast-specific protein-1, suggesting SC differentiation into smooth muscle cells or fibroblasts. Other STRO-1+ cells expressed the macrophage marker CD68, suggesting differentiation into inflammatory cells.

Conclusions: Stem cells are more abundant in TAAD tissue than in normal aortic tissue. Differentiation of SCs into smooth muscle cells, fibroblasts, and inflammatory cells within the diseased aortic wall suggests that SCs might be involved in both reparative and destructive remodeling processes in TAAD. Understanding the regulation of SC-mediated aortic remodeling will be a critical step toward designing strategies to promote aortic repair and prevent adverse remodeling.

Figure 1

Representative images of STRO-1+ cells detected by immunohistochemical staining in the medial and adventitial layers of control aortic, TAA, and TAD tissues (A; magnification, 400X). The mean densities of STRO-1+ cells in the media (B) and adventitia (C) were compared in the 3 groups. The relative distribution of STRO-1+ cells in the media and adventitia was compared in TAA (D) and TAD (E) tissues.

Figure 2

Representative images of c-kit+ cells detected by immunohistochemical staining in the medial and adventitial layers of control aortic, TAA, and TAD tissues (A; magnification, 400X). The mean densities of c-kit+ cells in the media (B) and adventitia (C) were compared in the 3 groups. The relative distribution of c-kit+ cells in the media and adventitia was compared in TAA (D) and TAD (E) tissues.

Figure 3

Representative images of CD34+ cells detected by immunohistochemical staining in the medial and adventitial layers of control aortic, TAA, and TAD tissues (A; magnification, 400X). The mean densities of CD34+ cells in the media (B) and adventitia (C) were compared in the 3 groups. The relative distribution of CD34+ cells in the media and adventitia was compared in TAA (D) and TAD (E) tissues.

Figure 4

Representative images (magnification, 400X) after double immunofluorescence staining showing the colocalization of the SMC marker SM22-α with STRO-1 (A), c-kit (B), or CD34 (C) in the medial layer of TAA tissue. Nuclei were counterstained with DAPI (blue).

Figure 5

Representative images (magnification, 400X) after double immunofluorescence staining showing the colocalizaton of the fibroblast marker FSP-1 with STRO-1 (A), c-kit (B), or CD34 (C) in the adventitial layer of TAA tissue. Nuclei were counterstained with DAPI (blue).

Figure 6

Representative images (magnification, 400X) of double immunofluorescence staining showing the colocalization of the macrophage marker CD68 with STRO-1 in the media and adventitia of TAA tissue. Nuclei were counterstained with DAPI (blue).