Localized expression of human BMP‐7 by BM‐MSCs enhances renal repair in an in vivo model of ischemia–reperfusion injury

Abstract

Ischemia and subsequent reperfusion (I ⁄ R) damage kidney tubular cells and consequently impair renal function. Rabbit bone marrow mesenchymal stem cells (BM-MSCs) expressing human bone morphogenic protein-7 (hBMP-7) regenerated tubular cells and improved renal function in a kidney I ⁄ R model. Rabbits were injected immediately after I ⁄ R with one of the following: (i) hBMP-7-transduced BM-MSCs (BM-MSCs hBMP-7 ); (ii) enhanced green fluorescent protein-transduced BM-MSCs (BM-MSCs EGFP ); or (iii) PBS. The activity of superoxide dismutase (SOD) was higher, and the amount of malondialdehyde (MDA) was lower in the BM-MSCs hBMP-7 group than in the BM-MSCs EGFP group. Both the BM-MSCs hBMP-7 group and the BM-MSCs EGFP group had higher SOD activity and lower amounts of MDA than the PBS group. Bcl-2-and Bcl-2-associated X protein levels, and other variables, indicated the regeneration of the kidney in both experimental groups. However, the BM-MSCs hBMP-7 group showed higher activity than the BM-MSCs EGFP group, indicating that the combined strategy of BM-MSC transplantation with hBMP-7 gene therapy could be a useful approach for the treatment of renal IRI.

Protective effects of recombinant human bone morphogenetic protein-7 on focal cerebral ischemia–reperfusion injury

“…Transcription of BMP-7 has also been found to change in kidney [13,17] and brain [9] tissues after IR. In addition, accumulating evidence suggests that exogenous BMP-7 can protect against ischemia-reperfusion injury in several tissues or organs, including kidney [18,19], brain [20], liver [21] and heart [14,22].…”

Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury

“…Although tissue-specific homing has been demonstrated in a number of different conditions, long-term engraftment of the MSCs has rarely been shown. Consequently, several studies have investigated strategies aimed at enhancing the MSC migratory properties, survival, and consequently regenerative capacity through preconditioning with various growth factors such as IGF-1 (66), glial cell-derived neurotrophic factor (GDNF) (52), melatonin (40), exposure to hypoxia (20), or genetic modification (10,12,16,69,71).…”

BMP-7 Signaling and its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease

“…Similar strategies have been suggested for the modulation of BMP agonists and antagonists in the kidney (Walsh et al, 2010). Finally, therapies utilizing mesenchymal stem cells have been proposed since these cells are recruited to the injured kidney, stimulate repair by secreting cytokines including BMP-7, and able to be genetically modified to produce high levels of BMP-7 (Humphreys & Bonventre, 2008;Lv et al, 2014;Zhen-Qiang et al, 2012).…”

“…This interest has intensified, as studies have demonstrated that BMP-7 not only inhibits the development of renal injuries but also stimulates the repair of established renal injuries. Indeed, treatment with recombinant BMP-7 is capable of promoting structural regeneration and functional recovery following acute renal injury (Zhen-Qiang et al, 2012) as well as reversing the progression of chronic renal injuries (Manson et al, 2011a(Manson et al, , 2011bMorrissey et al, 2002;Zeisberg, Hanai, et al, 2003;Zeisberg et al, 2005). The clinical prospects for the use of recombinant BMP-7 during the treatment of patients with CKD are enhanced by the existence of FDA-approved treatment protocols that utilize BMP-7 to promote the healing of bone fractures (White et al, 2007).…”