Abstract
IntroductionRenal disease affects over 500 million people worldwide and is set to increase as treatment options are predominately supportive. Evidence suggests that exogenous haematopoietic stem cells (HSCs) can be of benefit but due to the rarity and poor homing of these cells, benefits are either minor or transitory. Mechanisms governing HSC recruitment to injured renal microcirculation are poorly understood; therefore this study determined (i) the adhesion molecules responsible for HSC recruitment to the injured kidney, (ii) if cytokine HSC pre-treatment can enhance their homing and (iii) the molecular mechanisms accountable for any enhancement.MethodsAdherent and free-flowing HSCs were determined in an intravital murine model of renal ischaemia-reperfusion injury. Some HSCs and animals were pre-treated prior to HSC infusion with function blocking antibodies, hyaluronidase or cytokines. Changes in surface expression and clustering of HSC adhesion molecules were determined using flow cytometry and confocal microscopy. HSC adhesion to endothelial counter-ligands (VCAM-1, hyaluronan) was determined using static adhesion assays in vitro.ResultsCD49d, CD44, VCAM-1 and hyaluronan governed HSC adhesion to the IR-injured kidney. Both KC and SDF-1α pre-treatment strategies significantly increased HSC adhesion within injured kidney, whilst SDF-1α also increased numbers continuing to circulate. SDF-1α and KC did not increase CD49d or CD44 expression but increased HSC adhesion to VCAM-1 and hyaluronan respectively. SDF-1α increased CD49d surface clustering, as well as HSC deformability.ConclusionIncreasing HSC adhesive capacity for its endothelial counter-ligands, potentially through surface clustering, may explain their enhanced renal retention in vivo. Furthermore, increasing HSC deformability through SDF-1α treatment could explain the prolonged systemic circulation; the HSC can therefore continue to survey the damaged tissue instead of becoming entrapped within non-injured sites. Therefore manipulating these mechanisms of HSC recruitment outlined may improve the clinical outcome of cellular therapies for kidney disease.
Highlights
Renal disease affects over 500 million people worldwide and is set to increase as treatment options are predominately supportive
Increasing haematopoietic stem cells (HSCs) deformability through Stromal cell-derived factor-1a (SDF-1a) treatment could explain the prolonged systemic circulation; the HSC can continue to survey the damaged tissue instead of becoming entrapped within non-injured sites. Manipulating these mechanisms of HSC recruitment outlined may improve the clinical outcome of cellular therapies for kidney disease
Adherent and free flowing HSC numbers are increased in IR injured kidney Significantly (p,0.05) increased adhesion was observed in vitro on injured and contralateral (CL) renal sections taken from IR injured mice compared to sham tissue (Figure 1A)
Summary
Renal disease affects over 500 million people worldwide and is set to increase as treatment options are predominately supportive. Other BM-derived cells, such as mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) have shown to reduce fibrosis in more chronic renal disease models and clinical trials using BM-derived cells are currently ongoing [10,11,12,13]. This shows that exogenously injected stem cells are of benefit to both acutely and chronically injured mice
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