Patients with failing kidneys often suffer from chronic kidney disease or end-stage renal disease. These two conditions are associated with a substantial amount of suffering and death, and current treatments from chronic kidney disease and end-stage renal disease do virtually nothing to halt the progression of these diseases.
Fortunately there has been a respectable amount of recent work on kidney regeneration after kidney injury, but these new discoveries have not led to therapeutic advances. The shortage of kidneys for transplantation and the structural complexity of the kidney have slowed the development of therapeutic strategies for the kidney.
Stem cell-based therapy for damaged kidneys is a distinct possibility for several reasons. First, kidneys do seem to possess resident stem cells and extra renal stem cells also seem to reside in the kidney. Several studies have confirmed the presence of cells in the kidneys that possess stem cell-specific proteins (Sca-1, c-Kit, and CD133). When isolated and tested in the laboratory, these renal stem cells can differentiate, proliferate, and eventually reline denuded renal tubules, and thereby restore the structural and functional integrity of the kidney (See Yeagy BA, Cherqui S, Pediatr Nephrol 2011, 26:1427–1434; Parikh CR, et al., Ann Clin Biochem 2010, 47:301–312; Lee P-T, et al., Stem Cells 2010, 28:573–584; Bussolati B, et al., Am J Pathol 2005, 166:545–555; Dekel B, et al., J Am Soc Nephrol 2006, 17:3300–3314; Gupta S, et al., J Am Soc Nephrol 2006, 17:3028–3040; Lazzeri E, et al., J Am Soc Nephrol 2007, 18:3128–3138; and Kitamura S, et al., FASEB J 2005, 19:1789–1797). Unfortunately, the exact role of renal stem cells and their functional limitations and physiological niche are all subjects that are still being investigated.
Other work has shown that bone marrow stem cells can contribute to kidney repair after kidney injury (see Park HC, et al., Am J Physiol Renal Physiol 2010, 298:F1254–F1262; Cheng Z, et al., Mol Ther 2008, 16:571–579; and Qian H, et al., Int J Mol Med 2008, 22:325–332). It is unclear however, if bone marrow stem cells can trans-differentiate into renal stem cells.
To this end, a Chinese group has examined if bone marrow stem cells can actually trans-differentiate into renal stem cells after acute kidney injury. This work resulted from collaboration between the laboratories of Yong Xu at the Urology department at the Second Hospital of Tianjin Medical University, in Tianjin, China, and Zongjin Li at the School of Medicine at Nankai University in Tianjin, China.
In this study, workers from Xu’s and Li’s laboratories transplanted bone marrow stem cells from mice that expressed a glowing protein in their cells into mice that had been subjected to radiation. Radiation treatment wipes out the bone marrow of the mouse, and the transplantation reconstitutes the bone marrow. Therefore, the mice that were treated with radiation now have bone marrow stem cells that glow in the dark and anywhere those cells go, they will be traceable.
Once it was clear that the irradiated mice that had received the bone marrow transplantations had normal blood work (5 weeks later), their kidneys were subjected to acute damage by being deprived of sufficient blood flow for a short period of time. Four weeks later, the kidneys of these animals were examined in order to determine if the transplanted bone marrow stem cells had migrated to the kidneys to help heal them. A second experiment utilized a small protein called a “cytokine,” which acts as a powerful signal to stem cells. This particular cytokine, granulocyte colony stimulating factor (G-CSF), mobilizes stem cells from bone marrow such that the bone marrow stem cells move from their comfortable, leisurely existence to the bloodstream where they can go to help heal other tissues. By giving some of the transplanted mice doses of G-CSF, Xu and Li and their co-workers were able to determine if the bone marrow stem cells moved from the bone marrow to the kidney to take up residence in the kidney as the new renal stem cell population.
The results clearly showed that bone marrow stem cells moved from the bone marrow to the kidney to participate in kidney healing. However, it did not end there. These same labeled, glowing bone marrow stem cells expressed the proteins normally found in resident renal stem cells. While these bone marrow stem cells only constituted a small proportion of the renal stem cell population, they were clearly a part of the Sca-1+ or c-Kit+ renal progenitor cell population. Secondly, treatment with G-CSF almost doubled the frequency of bone marrow-derived renal stem cells in the kidney. G-CSF treatment also increased the capillary density in the injured kidney, which is significant, because bone marrow stem cells are rich in a population of blood vessel-making stem cells. Furthermore, the new blood vessels all glowed in the dark, which shows that they were made by the bone marrow-derived stem cells that moved to the kidney are contributed to the resident renal stem cell population that participated in kidney repair.
Thus, these data in this study establish that stem cells from bone marrow can trans-differentiate into cells that share many of the properties of renal resident stem cells. Furthermore, mobilization of these stem cells with cytokines like G-CSF mobilization can enhance the healing effects of these cells and might provide the basis for a new therapeutic strategy for end-stage renal disease or chronic kidney disease.