Int J Stem Cells.  2018 Nov;11(2):157-167. 10.15283/ijsc18073.

Hypoxic Preconditioned Mesenchymal Stromal Cell Therapy in a Rat Model of Renal Ischemia-reperfusion Injury: Development of Optimal Protocol to Potentiate Therapeutic Efficacy

• Jang MJ
• You D
• Park JY
• Kim K
• Aum J
• Lee C
• Song G
• Shin HC
• Suh N
• Kim YM
• Kim CS

• KMID: 2429548
• DOI: http://doi.org/10.15283/ijsc18073

Abstract

Although previous and ongoing clinical studies have used stromal cells during renal ischemia-reperfusion injury (IRI), there is little consensus regarding the optimal protocol. We aimed to optimize the protocol for hypoxic preconditioned human bone marrow-derived mesenchymal stromal cell (HP-hBMSC) therapy in a rat model of renal IRI. We determined the optimal injection route (renal arterial, renal parenchymal, and tail venous injection), dose (low-dose: 1×10⁶, moderate-dose: 2×10⁶, and high-dose: 4×10⁶), and injection period (pre-, concurrent-, and post-IRI). During optimal injection route study, renal arterial injections significantly reduced the decreasing glomerular filtration rate (GFR), as compared to GFRs for the IRI control group, 2 and 4 days after IRI. Therapeutic effects and histological recoveries were the greatest in the group receiving renal arterial injections. During the dose finding study, high-dose injections significantly reduced the decreasing GFR, as compared to GFRs for the IRI control group, 3 days after IRI. Therapeutic effects and histological recoveries were the greatest in the high-dose injection group. While determining the optimal injection timing study, concurrent-IRI injection reduced elevated serum creatinine levels, as compared to those of the IRI control group, 1 day after IRI. Pre-IRI injection significantly reduced the decreasing GFR, as compared with GFRs for the IRI control group, 1 day after IRI. Therapeutic effects and histological recoveries were the greatest in the concurrent-IRI group. In conclusion, the concurrent-IRI administration of a high dose of HP-hBMSC via the renal artery leads to an optimal recovery of renal function after renal IRI.

Keyword

Ischemia-reperfusion injury; Acute kidney injury; Hypoxia preconditioning; Cell therapy; Renal function

MeSH Terms

Acute Kidney Injury
Animals
Cell- and Tissue-Based Therapy
Consensus
Creatinine
Glomerular Filtration Rate
Humans
Mesenchymal Stromal Cells*
Models, Animal*
Rats*
Renal Artery
Reperfusion Injury*
Stromal Cells
Tail
Therapeutic Uses
Creatinine
Therapeutic Uses

Figure

• 

  Fig. 1 Representative flow cytometric histograms and morphology of HP-hBMSCs. (A) FACS data of HP-hBMSCs. (B) Passage 8 morphology of HP-hBMSCs, and differentiation via adipogenesis and osteogenesis.

• 

  Fig. 2 Serum BUN, serum creatinine, GFRs, histopathological scoring, and Sirius red staining of kidney tissue in optimal injection route study. Serial changes in levels of (A) serum BUN, (B) serum creatinine, and (C) GFRs. (D) H&E staining for histopathological score determination of each group in the kidney cortex and (E) medulla. Scale bar 50 μm. (F) Sirius red staining for determining degree of fibrosis for each group in the kidney cortex and (G) medulla. Scale bar 100 μm. NS, p>0.05; *, p<0.05; **, p<0.01; ***, and p<0.001, as compared with the IRI control group.

• 

  Fig. 3 Serum BUN, serum creatinine, GFRs, histopathological scoring, and Sirius red staining of kidney tissue in the dose finding study. Serial change in levels of serum BUN, (B) serum creatinine, and (C) GFRs. (D) H&E staining for histopathological score determination in each group in the kidney cortex and (E) medulla. Scale bar: 50 μm. (F) Sirius red staining for determining the degree of fibrosis of each group in the kidney cortex and (G) medulla. Scale bar: 100 μm. NS, p>0.05; *, p<0.05; **, p<0.01; ***, and p<0.001, as compared with the IRI control group.

• 

  Fig. 4 Serum BUN, serum creatinine, GFRs, histopathology scoring, and Sirius red staining of kidney tissue in optimal injection timing study. Serial changes in levels of (A) serum BUN levels, (B) serum creatinine levels, and (C) GFRs. (D) H&E staining for histopathological scoring of each group in the kidney cortex and (E) medulla. Scale bar: 50 μm. (F) Sirius red staining for determining the degree of fibrosis of each group in the kidney cortex and (G) medulla. Scale bar: 100 μm. NS, p>0.05; *, p<0.05; **, p<0.01; ***, and p<0.001. as compared with the IRI control group.

Reference

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