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. 2023 Feb;19(2):491-502.
doi: 10.1007/s12015-022-10443-8. Epub 2022 Sep 1.

Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys

Sarosh Siddiqi  1 , Nattawat Klomjit  1   2 , Kai Jiang  1 , Sabena M Conley  1 , Xianyang Zhu  1 , Ishran M Saadiq  1 , Christopher M Ferguson  1 , Hui Tang  1 , Amir Lerman  3 , Lilach O Lerman  4
Affiliations

Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys

Sarosh Siddiqi et al. Stem Cell Rev Rep. 2023 Feb.

Abstract

Clinical translation of mesenchymal stem/stromal cell (MSC) therapy has been impeded by the heterogenous nature and limited replicative potential of adult-derived MSCs. Human embryonic stem cell-derived MSCs (hESC-MSCs) that differentiate from immortal cell lines are phenotypically uniform and have shown promise in-vitro and in many disease models. Similarly, adipose tissue-derived MSCs (MSC(AT)) possess potent reparative properties. How these two cell types compare in efficacy, however, remains unknown. We randomly assigned mice to six groups (n = 7-8 each) that underwent unilateral RAS or a sham procedure (3 groups each). Two weeks post-operation, each mouse was administered either vehicle, MSC(AT)s, or hESC-MSCs (5 × 105 cells) into the aorta. Mice were scanned with micro-MRI to determine renal hemodynamics two weeks later and kidneys then harvested. hESC-MSCs and MSC(AT)s were similarly effective at lowering systolic blood pressure. However, MSC(AT)s more robustly increased renal perfusion, oxygenation, and glomerular filtration rate in the post-stenotic kidney, and more effectively mitigated tubular injury, fibrosis, and vascular remodeling. These observations suggest that MSC(AT) are more effective than hESC-MSC in ameliorating kidney dysfunction and tissue injury distal to RAS. Our findings highlight the importance of tissue source in selection of MSCs for therapeutic purposes and underscore the utility of cell-based therapy for kidney disease.

Keywords: mesenchymal stem/stromal cells; mouse; renal artery stenosis.

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Conflict of interest statement

Conflicts of Interest

Dr. Lerman is an advisor to AstraZeneca, CureSpec, and Butterfly Biosciences. The authors declare no conflict.

Figures

Figure 1.
Figure 1.
(A,B). Both hESC-MSCs and MSC(AT)s expressed the typical MSC markers CD90, CD105, and CD73, and were negative for CD45 and CD34. (C) Successful in-vitro differentiation into adipocytes (left), osteocytes (middle), and chondrocytes (right) confirmed the multi-potency of both cell types. (D) , hESC-MSC showed higher differentiation into adipocytes and osteocytes than MSC(AT).
Figure 2.
Figure 2.
(A) The increase in systolic blood pressure (BP) in RAS+vehicle was greater compared to sham+vehicle, whereas changes in RAS+MSC(AT) and RAS+hESC-MSC were indistinguishable from sham+vehicle. (B) Plasma creatinine levels were similarly elevated compared to sham+vehicle in RAS+hESC-MSC and RAS+vehicle, but not in RAS+MSC(AT). (C) Plasma renin content remained elevated in RAS+hESC-MSC but returned to sham levels in RAS+MSC(AT). *p≤0.05 vs. sham+vehicle, ⱡp≤0.05 vs. RAS+vehicle, &p≤0.05 vs. RAS+MSC(AT). sham+vehicle n=5-8, sham+MSC(AT) n=5-6, sham+hESC-MSC n=4-7, RAS+vehicle n=5-8, RAS+MSC(AT) n=6-8, RAS+hESC-MSC n=5-8.
Figure 3.
Figure 3.
In vivo micro-magnetic resonance imaging at 4 weeks. (A) Representative renal perfusion and hypoxia maps obtained using arterial spin labeling and blood oxygenation level dependent magnetic resonance imaging, respectively. Increasing yellow color indicates higher perfusion, and increasing red means greater hypoxia. (B) Cortical perfusion in untreated post-stenotic kidneys (STK) was reduced compared to sham+vehicle. It normalized after administration of MSC(AT)s, but remained significantly lower than sham+vehicle after hESC-MSCs delivery. (C) Medullary perfusion was significantly below sham+vehicle in all RAS groups and remained unaltered after delivery of hESC-MSC and MSC(AT). (D,E) RAS+vehicle manifested cortical and medullary hypoxia. MSC(AT)-treated mice tended to show lower cortical and medullary hypoxia (both p=.01) than hESC-MSC treated mice and were comparable to sham+vehicle. Fluid-filled collection system structures (blue) were excluded from analysis. (F) Ratio of STK/contralateral kidney weight ex-vivo was reduced in RAS+vehicle and improved in RAS+MSC(AT). *p≤0.05 vs. sham+vehicle, ⱡp≤0.05 vs. RAS+vehicle, &p≤0.05 vs. RAS+MSC(AT). sham+vehicle n=7, sham+MSC(AT) n=5, sham+hESC-MSC n=7, RAS+vehicle n=7, RAS+MSC(AT) n=6-7, RAS+hESC-MSC n=6-7.
Figure 4.
Figure 4.
(A,B) RAS mice administered MSC(AT) retained a similar number of cells as sham mice, whereas RAS+hESC-MSC retained significantly more cells than any other group. (A,C) Co-localization of MSCs (pink arrows) and CD3+ cells (green arrows) was uncommon, with no significant differences among groups. &p≤0.05 vs. RAS+MSC(AT). sham+MSC(AT) n=5-6, sham+hESC-MSC n=6, RAS+MSC(AT) n=6-7, RAS+hESC-MSC n=5-6.
Figure 5.
Figure 5.
(A) Representative H&E and trichrome stained kidney sections. (B) MSC(AT)s were more effective than hESC-MSCs at reducing tubular injury in RAS mice kidneys, yet both cell types caused small but significant tubular injury in sham kidneys. (C) MSC(AT)s were more effective at reducing fibrosis in RAS than hESC-MSCs, although neither lowered it to sham+vehicle levels. In sham mice, hESC-MSCs provoked to greater fibrosis than vehicle (D) Both cell types dramatically lowered glomerulosclerosis in RAS kidneys but slightly increased it in sham. *p≤0.05 vs. sham+vehicle, ⱡp≤0.05 vs. RAS+vehicle, &p≤0.05 vs. RAS+MSC(AT). sham+vehicle n=6, sham+MSC(AT) n=6-7, sham+hESC-MSC n=6-7, RAS+vehicle n=6, RAS+MSC(AT) n=6-7, RAS+hESC-MSC n=5-6.
Figure 6.
Figure 6.
(A) Representative immunohistochemical staining of kidney sections for CD31 and α-SMA. (B) Both hESC-MSCs and MSC(AT)s improved peritubular capillary density in RAS mice. (C) MSC(AT)s and hESC-MSCs both reduced media-to-lumen ratio significantly in RAS, with MSC(AT)s restoring it to sham+vehicle levels. *p≤0.05 vs. sham+vehicle, ⱡp≤0.05 vs. RAS+vehicle, &p≤0.05 vs. RAS+MSC(AT). sham+vehicle n=6, sham+MSC(AT) n=6, sham+hESC-MSC n=6, RAS+vehicle n=5, RAS+MSC(AT) n=6, RAS+hESC-MSC n=6.
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