Therapeutic potential of stromal cells of non-renal or renal origin in experimental chronic kidney disease

Abstract

BackgroundMesenchymal stromal cell (MSC)-based therapy is a promising strategy for preventing the progression of chronic kidney disease (CKD), with the potential to induce tissue regeneration. In search of the best cellular source we compared, in the rat model of adriamycin (ADR) nephropathy, the regenerative potential of human stromal cells of non-renal origin, such as bone marrow (bm) MSCs and umbilical cord (uc) MSCs, with that of newly discovered stromal cells of renal origin, the kidney perivascular cells (kPSCs) known to exhibit tissue-specific properties.MethodsThe therapeutic effect of repeated infusions of human bmMSCs, ucMSCs, kPSCs (1.5 × 106 cells/rats) or conditioned medium from ucMSCs was studied in athymic rats with ADR-induced nephropathy (7.9 mg/kg). The ability of the three stromal cell populations to engraft the damaged kidney was evaluated by detecting the presence of human nuclear antigenpos cells. Glomerular podocyte loss and endothelial damage, sclerotic lesions and inflammation were assessed at 14 and 28 days. In-vitro experiments with a transwell system were performed to investigate the effects of different stromal cell populations on parietal epithelial cells (PECs) activated or not with albumin or angiotensin II for 24 h.ResultsInfusions of non-renal and renal stromal cells resulted in a comparable engraftment into the kidney, in the peritubular areas and around the glomerular structures. All three cell populations limited podocyte loss and glomerular endothelial cell injury, and attenuated the formation of podocyte and PEC bridges. This translated into a reduction of glomerulosclerosis and fibrosis. Human ucMSCs had an anti-inflammatory effect superior to that of the other stromal cells, reducing macrophage infiltration and inducing polarisation towards the M2 macrophage phenotype. Conditioned medium from ucMSCs shared the same renoprotective effects of the cells. Consistent with in-vivo data, bmMSCs and kPSCs, but even more so ucMSCs, limited proliferation, migratory potential and extracellular matrix production of activated PECs, when cultured in a transwell system.ConclusionsOur data indicate that either non-renal or renal stromal cells induce renal tissue repair, highlighting ucMSCs and their conditioned medium as the most reliable clinical therapeutic tool for CKD patients.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0960-8) contains supplementary material, which is available to authorized users.

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…Similar to what has been reported in regard to the effectiveness of MSCs, with some tissue sources preferable for certain indications (e.g., umbilical cord MSCs for immunomodulatory tasks [ 33 ] and BMSCs for bone regeneration [ 2 ] ), the tissue of origin also impacts the effectiveness of the MSC secretome. First, there is a significant difference in the levels of soluble factors and EVs secreted by MSCs according to their tissue of origin [ 124,242 ] and MSCs secrete EVs enriched in distinct miRNA and tRNA species [ 243 ] and proteins [ 242 ] according to their tissue of origin.…”

“…Together, these offer a repertoire of opportunities to obtain MSCs possessing therapeutic potential. In addition to the most commonly employed MSC sources for cell therapy noted here, organ‐specific resident MSCs have been identified, e.g., in the lung, [ 60 ] kidney, [ 33 ] and liver, [ 61 ] which could be involved in tissue healing and may have potential applications in cell therapeutics. Created with BioRender.com.…”

The effect of transplantation of bone marrow cells induced by the contact with thymus-derived multipotent stromal cells on the immune system of mice, regenerating after cyclophosphamide treatment

“…Thus, as a result of induced BMCs administration, but not intact BMCs, into mice treated with cyclophosphamide showed partial normalization of cellular parameters in various organs of the immune system. The efficacy of MSCs as an inductors of HSCs at bone marrow transplantation may be explained by the contact interaction of HSCs and stromal cells, as well as by the production of cytokines and growth factors necessary for homing and differentiation of HSCs [20,21].…”

“…Experiments were conducted on male C57BL/6 mice aged 6-8 weeks and weighing 18-20 g from the vivarium of Kavetsky Institute of Pathology, Oncology and Radiobiology of the National Academy of Sciences of Ukraine, which received a balanced diet and had free access to water ad libitum. All studies on experimental animals were carried out in compliance with the requirements of Article 26 of the Law of Ukraine «On the Protection of Animals from Cruelty» (February 21,2006) and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (Strasbourg, 1986) To study the effect of cells on regeneration of the immune system of syngeneic mice, four groups were formed: I -normal animals, control (n = 10), II -mice with cyclophosphamide treatment (n = 9), ІІІ -animals with cyclophosphamide treatment receiving BMCs (n = 7) and IV -with cyclophosphamide treatment receiving BMCs, induced by a previous 2-hour contact with MSCs (iBMCs) (n = 8).…”

Mesenchymal Stem Cells in Renal Fibrosis: The Flame of Cytotherapy

“…It is widely agreed that transplanted MSCs can directly reconstruct impaired organs [28]. MSCs are also capable of producing cytokines, growth factors, and chemokines; moreover, they exert a comprehensive range of functions by expressing extracellular matrix receptors on their cell surface, including antiapoptosis [29], angiogenesis [30], anti-inflammation [31], immune regulation [32], antiscarring [33], and chemically induced homing to damaged tissue, thus supporting the growth and differentiation of diseased cells, which makes them attractive for clinical applications. Fibrosis, as one of the most common and refractory pathological processes, has always drawn substantial attention, and many efforts and trials of MSC cellular therapy have been carried out on antifibrotic diseases [34].…”