Will it be Possible to Generate Kidney Tissue from Induced Pluripotent Stem Cells for Regenerative Therapy?

Abstract

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. The increased prevalence of CKD has led to a rise in the number of dialysis patients, and is associated with elevated morbidity and mortality due to the increased risk of cardiovascular disease [1]. Regenerative medicine strategies are highly anticipated for CKD, since patients with CKD never recover their renal function, and there are no radical treatments besides renal transplantation. With this as the goal, vigorous efforts have been made for the directed differentiation of mouse embryonic stem cells (mESCs) [2,3] into kidney lineage cells, while research using human ESCs [4] or induced pluripotent stem cells (hiPSCs) [5,6] has not been fully developed [7]. By mimicking signals that occur during embryonic development, to the extent that they are known, a stepwise protocol was explored to differentiate pluripotent stem cells (PSCs) into clinically useful cell types in adult organs. Currently, most of the studies aiming to generate renal cells from PSCs have also adopted the strategy of mimicking renal development [7]. The kidneys are derived from an early embryonic germ layer, the intermediate mesoderm (IM) that is located between the lateral and paraxial mesoderms [8]. In vertebrates, the IM successively develops three kidneys: the pronephros, mesonephros and metanephros. The three kidneys are similar in that they consist of a basic functional unit, the nephron, although the number of nephron differs among the kidneys. The mammalian adult kidney, metanephros, is formed by the reciprocal interaction between two tissues derived from the IM, the metanephric mesenchyme and ureteric bud. The ureteric bud induces the metanephric mesenchyme to differentiate into nephrons and interstitium. The nephron progenitors in metanephric mesenchyme differentiate into epithelia constituting glomeruli, proximal or distal renal tubules, or Henle’s loop. The metanephric mesenchyme may contain at least two other precursor populations, in addition to the epithelial progenitors: vascular precursor cells that give rise to vascular and glomerular endothelia and vascular smooth muscle cells; and stromal precursors that eventually differentiate into interstitial cells within the adult kidney. The ureteric bud elaborates the lower urinary tract system, from the collecting ducts through the renal pelvis and ureters, to a part of the urinary bladder [8]. Most of the mechanisms underlying the lineage commitment, by which the IM gives rise to the metanephric mesenchyme and ureteric bud, and how the two precursors differentiate into adult renal cell types, are unknown. Further examinations will be required to elucidate the mechanisms, which will eventually help reproduce the tissues in vitro from PSCs. Our group has recently published a report on the highly efficient differentiation of human PSCs into IM cells [9]. These human IM cells have the developmental potential to further differentiate into adult and embryonic renal cells, such as glomerular podocytes, proximal renal tubular cells and ureteric bud cells. Furthermore, they can form 3D renal tubular structures when co-cultured with mouse metanephric cells in organ culture settings. However, the efficiency of tubule formation is very low, at around 5% of the organ cultures. We reasoned that this observed low efficiency resulted from the developmental immaturity of the IM cells. Therefore, our group is currently developing efficient differentiation protocols from human PSC-derived IM cells into the two kidney