Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 22;14(1):49.
doi: 10.1186/s13287-023-03269-9.

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells

Xiaohui Bian #  1   2 , Sabena M Conley #  1 , Alfonso Eirin  3 , Eric A Zimmerman Zuckerman  4 , Anastasia L Smith  1 , Cody C Gowan  1 , Zachary K Snow  1 , Tambi Jarmi  5 , Houssam Farres  6 , Young M Erben  6 , Albert G Hakaim  6 , Matthew A Dietz  7 , Abba C Zubair  8   9 , Saranya P Wyles  10 , Joy V Wolfram  11   12 , Lilach O Lerman  3 , LaTonya J Hickson  13   14
Affiliations

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells

Xiaohui Bian et al. Stem Cell Res Ther. .

Abstract

Background: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach.

Methods: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state.

Results: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm).

Conclusions: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia.

Keywords: Chronic kidney disease; Diabetes mellitus; Diabetic nephropathy; Ischemic limb disease; Mesenchymal stromal cells; Regenerative medicine.

PubMed Disclaimer

Conflict of interest statement

Lilach Lerman, MD, PhD, received grant funding from Novo Nordisk and is an advisor to Weijian Technologies and AstraZeneca. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow cytometric characterization of passage 3 mesenchymal stromal cells (MSC) isolated from adipose tissue of diabetic kidney disease (DKD) subjects which were positive for MSC-specific surface markers cluster of differentiation (CD)90, CD105, and CD73 and were negative for hematopoietic cell markers, CD34 and CD14. BF, Brightfield
Fig. 2
Fig. 2
The volcano plot demonstrates the distribution of the top 30 differentially expressed (DE) upregulated (red) and down-regulated (green) angiogenesis-related genes (A). Heatmaps are shown for DE upregulated (B) and down-regulated (C) mRNAs in DKD-MSC. padj: adjusted p value
Fig. 3
Fig. 3
Heatmap demonstrates 14 DE microRNAs (miRNAs) in DKD-MSC (A). Table lists differentially expressed miRNA and their potential angiogenesis-related mRNA targets analyzed by ingenuity pathway analysis (B). Font colors: upregulated (red), down-regulated (green) miRNAs. Diagram of let-7a-5p targeting of several mRNAs including TAGLN, THBS1, LOXL4, COL4A1, and COL8A1 in addition to other differentially expressed miRNA activities (C)
Fig. 4
Fig. 4
Representative images of capillary-like tubes formed by non-injured human umbilical vein endothelial cells (HUVEC) or in the presence of high glucose (HG) plus indoxyl sulfate (IS) injury and either Control-MSC conditioned medium (cm) or DKD-MSCcm. Images were acquired at 40× resolution and were not enhanced. (A). Quantification of total number of tubes among groups (B). Selectin E (SELE), vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM-1) (C) and vascular endothelial growth factor (VEGF) (D) mRNA expression levels in HUVEC. ns, not statistically significant (p > 0.5); other non-significant p values (p > 0.05) are shown in this figure given trends in the relationships
See this image and copyright information in PMC

References

    1. Saran R, Robinson B, Abbott KC, Bragg-Gresham J, Chen X, Gipson D, et al. US renal data system 2019 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2020;75(1 Suppl 1):A6–A7. doi: 10.1053/j.ajkd.2019.09.003. - DOI - PubMed
    1. Kim SR, Zou X, Tang H, Puranik AS, Abumoawad AM, Zhu XY, et al. Increased cellular senescence in the murine and human stenotic kidney: effect of mesenchymal stem cells. J Cell Physiol. 2021;236(2):1332–1344. doi: 10.1002/jcp.29940. - DOI - PMC - PubMed
    1. Yu S, Kim SR, Jiang K, Ogrodnik M, Zhu XY, Ferguson CM, et al. Quercetin reverses cardiac systolic dysfunction in mice fed with a high-fat diet: role of angiogenesis. Oxid Med Cell Longev. 2021;2021:8875729. doi: 10.1155/2021/8875729. - DOI - PMC - PubMed
    1. Bian X, Griffin TP, Zhu X, Islam MN, Conley SM, Eirin A, et al. Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy. BMJ Open Diabetes Res Care. 2019;7(1):e000720. doi: 10.1136/bmjdrc-2019-000720. - DOI - PMC - PubMed
    1. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446–456. doi: 10.1016/j.ebiom.2019.08.069. - DOI - PMC - PubMed

Publication types

MeSH terms