construction-human-aorta-smooth-muscle-cell-organ-on-chip-model-for

Construction of a Human Aorta Smooth Muscle Cell Organ-On-A-Chip Model for Recapitulating Biomechanical Strain in the Aortic Wall

Conventional two-dimensional cell culture techniques and animal models have been used in the study of human thoracic aortic aneurysm and dissection ...

Fudan University

The aorta is the largest artery in the body, so any diseases or conditions which could cause damage to the aorta would put patients at considerable and life-threatening risk. In the management of aortic diseases, the major treatments include drug therapy, endovascular treatment, and surgical treatment, which are of great danger or with a poor prognosis. The delivery of nano-biomaterials provides a potential development trend and an emerging field where we could monitor patients' conditions and responses to the nanotherapeutics. One of the putative applications of nanotechnology is ultrasensitive monitoring of cardiovascular markers by detecting and identifying aneurysms. Moreover, the use of nanosystems for targeted drug delivery can minimize the systemic side effects and enhance drug positioning and efficacy compared to conventional drug therapies. This review shows some examples of utilizing nano-biomaterials in  organ and cell culture experiments and explains some developing technologies in delivering and monitoring regenerative therapeutics.

Nano-Biomaterials for the Delivery of Therapeutic and Monitoring Cues for Aortic Diseases.

Colon cancer is one of the most common cancers, great progress was taken place in the treatment of colon cancer, however, the prognostic assessment system remains lagging. Cell cycle plays a vital role in the whole procedure of cancers. In this study, we firstly identified cell cycle-related genes specific in colon cancer. Functional enrichment analysis proved our analysis reliable. Furthermore, we constructed a robust signature based on the cell cycle-related genes. The AUC of the signature to predict the overall survival was 0.808, 0.807, and 0.831 of AUC at 1, 3, and 5 years, respectively. Internal and external validation proved the signature efficient. The 9 genes involved in the signature also showed a great job in molecular subgrouping which indicated the significant value of the 9 genes for further experimental research. In conclusion, the present research provided a novel robust signature predicting the prognosis of colon cancer.

Construction and Validation of a Cell Cycle-Related Robust Prognostic Signature in Colon Cancer.

Aortic aneurysm is a common cardiovascular disease characterised by continuous dilation of the aorta, and this disease places a heavy burden on healthcare worldwide. Few drugs have been suggested to be effective in controlling the progression of aortic aneurysms. Preclinical drug responses from traditional cell culture and animals are usually controversial. An effective  model is of great demand for successful drug screening. In this study, we induced an  microphysiological system to test metformin, which is a potential drug for the treatment of aortic aneurysms. Human pluripotent stem cell-derived aortic smooth muscle cells (hPSC-HASMCs) were cultured on an  microphysiological system, which could replicate the cyclic stretch of the human native aortic wall. By using this system, we found that HASMCs were more likely to present a physiologically contractile phenotype compared to static cell cultures. Moreover, we used hPSC-HASMCs in our microphysiological system to perform metformin drug screening. The results showed that hPSC-HASMCs presented a more contractile phenotype via NOTCH 1 signalling while being treated with metformin. This result indicated that metformin could be utilised to rescue hPSC-HASMCs from phenotype switching during aortic aneurysm progression. This study helps to elucidate potential drug targets for the treatment of aortic aneurysms.

Engineering a Human Pluripotent Stem Cell-Based  Microphysiological System for Studying the Metformin Response in Aortic Smooth Muscle Cells.

Aortic aneurysm (AA) remains one of the primary causes of death worldwide. Of the major treatments, prophylactic operative repair is used for AA to avoid potential aortic dissection or rupture. To halt the development of AA and alleviate its progression into aortic dissection, pharmacological treatment has been investigated for years. Currently, β-adrenergic blocking agents, losartan, irbesartan, angiotensin-converting-enzyme inhibitors, statins, antiplatelet agents, doxycycline, and metformin have been investigated as potential candidates for preventing AA progression. However, the paradox between preclinical successes and clinical failures still exists, with no medical therapy currently available for ideally negating the disease progression. This review describes the current drugs used for pharmacological management of AA and their individual potential mechanisms. Preclinical models for drug screening and evaluation are also discussed to gain a better understanding of the underlying pathophysiology and ultimately find new therapeutic targets for AA.

Current Pharmacological Management of Aortic Aneurysm.

Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease.

Patients with bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation (AAD). Our study was aimed at systemically analyzing the expression profile and mechanism of circulating plasma exosomal microRNAs (miRNAs) related to BAV and AAD.

Plasma Exosomal Mir-423-5p Is Involved in the Occurrence and Development of Bicuspid Aortopathy  TGF-β/SMAD2 Pathway.

To investigate the feasibility of a pre-targeted imaging strategy based on the cycloaddition between 1,2,4,5-terazine (Tz) and trans-cyclooctene (TCO) for evaluating CD11b expression in inflammatory aortic aneurysm (AA) using single photon emission computed tomography/computed tomography (SPECT/CT).

CD11b-Based Pre-Targeted SPECT/CT Imaging Allows for the Detection of Inflammation in Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is the permanent dilation of the thoracic aortic wall that predisposes patients to lethal events such as aortic dissection or rupture, for which effective medical therapy remains scarce. Human-relevant microphysiological models serve as a promising tool in drug screening and discovery.

Article	Year
Nano-Biomaterials for the Delivery of Therapeutic and Monitoring Cues for Aortic Diseases. Frontiers in bioengineering and biotechnology\| PubMed ID: 33224934	2020
Construction and Validation of a Cell Cycle-Related Robust Prognostic Signature in Colon Cancer. Frontiers in cell and developmental biology\| PubMed ID: 33304907	2020
Engineering a Human Pluripotent Stem Cell-Based Microphysiological System for Studying the Metformin Response in Aortic Smooth Muscle Cells. Frontiers in bioengineering and biotechnology\| PubMed ID: 33816448	2021
Current Pharmacological Management of Aortic Aneurysm. Journal of cardiovascular pharmacology\| PubMed ID: 33990514	2021
Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease. eLife\| PubMed ID: 34486519	2021
Plasma Exosomal Mir-423-5p Is Involved in the Occurrence and Development of Bicuspid Aortopathy TGF-β/SMAD2 Pathway. Frontiers in physiology\| PubMed ID: 34955881	2021
CD11b-Based Pre-Targeted SPECT/CT Imaging Allows for the Detection of Inflammation in Aortic Aneurysm. Journal of inflammation research\| PubMed ID: 35321320	2022
Patient-derived microphysiological model identifies the therapeutic potential of metformin for thoracic aortic aneurysm. EBioMedicine\| PubMed ID: 35636318	2022

Shichao Zhu

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