Advances and challenges in regenerative therapies for abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a significant source of mortality worldwide and carries a mortality of greater than 80% after rupture. Despite extensive efforts to develop pharmacological treatments, there is currently no effective agent to prevent aneurysm growth and rupture. Current treatment paradigms only rely on the identification and surveillance of small aneurysms, prior to ultimate open surgical or endovascular repair. Recently, regenerative therapies have emerged as promising avenues to address the degenerative changes observed in AAA. This review briefly outlines current clinical management principles, characteristics, and pharmaceutical targets of AAA. Subsequently, a thorough discussion of regenerative approaches is provided. These include cellular approaches (vascular smooth muscle cells, endothelial cells, and mesenchymal stem cells) as well as the delivery of therapeutic molecules, gene therapies, and regenerative biomaterials. Lastly, additional barriers and considerations for clinical translation are provided. In conclusion, regenerative approaches hold significant promise for in situ reversal of tissue damages in AAA, necessitating sustained research and innovation to achieve successful and translatable therapies in a new era in AAA management.

Keywords: abdominal aortic aneurysm; biomaterials; cellular therapy; regenerative medicine; vascular surgery.

Figure 1

Regenerative therapies for the management of abdominal aortic aneurysm. Illustrations in top right panel adapted with permission from [Kyriacou et al. (15)], licensed under CC BY 4.0, https://doi.org/10.1177/1750458920947352. Created with BioRender.com.

Figure 2

Schema of cellular and molecular processes involved in abdominal aortic aneurysm (AAA) pathogenesis. Extracellular matrix (ECM) degradation, vascular smooth muscle cell (VSMC) dysfunction, and inflammation are present throughout the aortic wall. Each presents a potential target for regenerative medicine strategies. Created with BioRender.com.

Figure 3

Cellular therapy strategies to regenerate vascular tissues in AAA. Cell therapies using VSMCs, ECs, and MSCs have each demonstrated therapeutic benefits for AAA treatment. These cells can be derived from iPSCs or collected from peripheral blood and allogenic/autologous tissue sources such as bone marrow and adipose tissue. Route of delivery, intravascular and periadventitial, are both feasible approaches with their own respective advantages and challenges. Cells exert regenerative effects via several mechanisms including direct engraftment, immunomodulation, paracrine signaling, and ECM synthesis which result in restored elastin, reduced protease activity, reendothelialization, and reduced inflammation. Created with BioRender.com.

Figure 4

Fate of MSCs after periadventitial delivery. (A) Engraftment and differentiation of MUSE (GFP+) cells into SMCs (αSMA+, top) and endothelial cells (CD31+, bottom) 3 weeks after periadventitial delivery. Reprinted from (87) with permission from Elsevier, © 2018 by The American Association for Thoracic Surgery, https://doi.org/10.1016/j.jtcvs.2018.01.098. (B) Periadventitial delivery of ADSCs using recombinant collagen peptide patches (top right). Labeled ADSCs (red, arrows) could be visualized throughout the aortic wall after 14 days (bottom right) but not bare control patches (bottom left) (* = autofluorescence of the elastic laminae). Reprinted from (88) with permission from Elsevier, © 2018 Wiley Periodicals, Inc., https://doi.org/10.1002/jbm.a.36445.

Figure 5

Cell-free regenerative approaches to attenuate AAA. Products derived from cells, including extracellular vesicles or mitochondria, offer the therapeutic paracrine effects of cells while avoiding some of the translational barriers of cell therapies. Gene therapy offers precise control of molecular mechanisms. Controlled delivery of proteins and drugs provides targeted and sustained therapeutic effects, while protecting payloads from rapid degradation in the inflammatory environment. Biomaterials are typically paired with a molecular or cellular payload but can also offer regenerative potential alone. Created with BioRender.com.