Human liver derived mesenchymal stromal cells ameliorate murine ischemia-induced inflammation through macrophage polarization

• Published in: Frontiers in immunology Vol. 15; p. 1448092
• Main Authors: Liang, Yun, Ozdogan, Elif, Hansen, Michael J, Tang, Hui, Saadiq, Ishran, Jordan, Kyra L, Krier, James D, Gandhi, Deep B, Grande, Joseph P, Lerman, Lilach O, Taner, Timucin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 22-07-2024
• Subjects: Animals; Disease Models, Animal; Humans; Immunology; immunomodulation; inflammation; Inflammation - immunology; Inflammation - therapy; Ischemia - immunology; Ischemia - therapy; Kidney - immunology; Kidney - pathology; Liver - immunology; Liver - pathology; liver tolerance; Macrophage Activation; Macrophages - immunology; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells; mesenchymal stromal cells; Mice; Renal Artery Obstruction - immunology; Renal Artery Obstruction - therapy; renal artery stenosis; immunomodulation; renal artery stenosis; inflammation; mesenchymal stromal cells; liver tolerance
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1448092

The immunomodulatory properties of mesenchymal stromal cells (MSC) have been well-characterized in
and
models. We have previously shown that liver MSC (L-MSC) are superior inhibitors of T-cell activation/proliferation, NK cell cytolytic function, and macrophage activation compared to adipose (A-MSC) and bone marrow MSC (BM-MSC)
.
To test these observations
, we infused these types of MSC into mice with unilateral renal artery stenosis (RAS), an established model of kidney inflammation. Unilateral RAS was induced via laparotomy in 11-week-old, male 129-S1 mice under general anesthesia. Control mice had sham operations. Human L-MSC, AMSC, and BM-MSC (5x105 cells each) or PBS vehicle were injected intra-arterially 2 weeks after surgery. Kidney morphology was studied 2 weeks after infusion using micro-MRI imaging. Renal inflammation, apoptosis, fibrosis, and MSC retention were studied
utilizing western blot, immunofluorescence, and immunohistological analyses.
The stenotic kidney volume was smaller in all RAS mice, confirming significant injury, and was improved by infusion of all MSC types. All MSC-infused groups had lower levels of plasma renin and proteinuria compared to untreated RAS. Serum creatinine improved in micetreated with BM- and L-MSC. All types of MSC located to and were retained within the stenotic kidneys, but L-MSC retention was significantly higher than A- and BM-MSC. While all groups of MSC-treated mice displayed reduced overall inflammation and macrophage counts, L-MSC showed superior potency
at localizing to the site of inflammation and inducing M2 (reparative) macrophage polarization to reduce inflammatory changes.
These
findings extend our
studies and suggest that L-MSC possess unique anti-inflammatory properties that may play a role in liver-induced tolerance and lend further support to their use as therapeutic agents for diseases with underlying inflammatory pathophysiology.