Kidney Week

Abstract: TH-PO417

Thrombomodulin-Overexpressing Adipose-Derived Mesenchymal Stem Cells Prevent Thromboembolism and Ameliorate Kidney Fibrosis in Rats

Session Information

• Development, Organoids, Injury, and Regeneration
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Tanaka, Yoshiki, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan

Yoshiki Tanaka, MD

• Nakashima, Ayumu, Yamanashi Daigaku, Kofu, Yamanashi, Japan

Ayumu Nakashima, MD, PhD, FASN

• Ishiuchi, Naoki, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan

Naoki Ishiuchi, DrMed

• Miyasako, Kisho, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan

Kisho Miyasako, DrMed

• Morimoto, Keisuke, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan

Keisuke Morimoto

• Sasaki, Kensuke, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan

Kensuke Sasaki, MD, PhD

• Masaki, Takao, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan

Takao Masaki, MD, PhD

Background

Adipose-derived mesenchymal stem cells (ASCs) exhibit anti-inflammatory and anti-fibrotic effects via their
paracrine action, and thereby are expected to be a new therapy for kidney disease. Meanwhile, ASCs
reportedly exhibit procoagulant activity compared to other mesenchymal stem cell types, raising concerns
about thrombogenic risk. Thrombomodulin (TM) on the cell surface acts as an anticoagulant and
antifibrinolytic factor by binding to thrombin, a procoagulant factor. This led us to the hypothesis that ASCs
overexpressing TM can be safely used for cell therapy by reducing the risk of thromboembolism.

Methods

ASCs infected with adeno-associated virus (AAV) carrying TM cDNA or an empty AAV were designated as “TM-ASC” or “null-ASC”, respectively. To examine the risk of renal infarction induced by ASCs, 5.0×10⁵ ASCs were administered via renal artery into rats with unilateral ischemia reperfusion injury (IRI) and contralateral nephrectomy (renal infarction model). To assess the risk of pulmonary embolism caused by ASCs, 7.5×10⁶ ASCs were injected into rats via tail vein (pulmonary embolism model). Additionally, we examined the anti-inflammatory and anti-fibrotic effects of TM-ASC using IRI rats treated with TM-ASC and null-ASC.

Results

In the renal infarction model, 36% (n = 4/11) of the rats in the null-ASC group died by day 3, whereas all of
rats (n = 11/11) in the TM-ASC group were alive. In the pulmonary embolism model, 40% (n = 3/12) of the
rats in the null-ASC group died within 24 hours, while all of rats (n = 12/12) in the TM-ASC group were
alive. Intravascular thrombus was identified in 30/120 fields in the null-ASC group and decreased to 3/120
fields in the TM-ASC group in hematoxylin and eosin staining of rat lung tissues. In addition, administration of TM-ASC more
potently alleviated renal inflammation and fibrosis induced by IRI compared to that of null-ASC.

Conclusion

These findings indicate that TM-overexpressing ASCs not only increase treatment safety, but also enhance their therapeutic efficacy. Administration of TM-overexpressing ASCs is a promising therapeutic strategy to prevent progression from organ damage to failure.