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A Novel Three–Dimensional Human Peritubular Microvascular System

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A Novel Three–Dimensional Human Peritubular Microvascular System BASIC RESEARCH www.jasn.org A Novel Three–Dimensional Human Peritubular Microvascular System Giovanni Ligresti,*† Ryan J. Nagao,* Jun Xue,* Yoon Jung Choi,* Jin Xu,* Shuyu Ren,† Takahide Aburatani,† Susan K. Anderson,† James W. MacDonald,‡ Theo K. Bammler,‡ Stephen M. Schwartz,§ Kimberly A. Muczynski,† Jeremy S. Duffield,†| Jonathan Himmelfarb,†| and Ying Zheng*¶ Departments of *Bioengineering, †Medicine, ‡Environmental and Occupational Health Sciences, and §Pathology, |Kidney Research Institute, and ¶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington ABSTRACT Human kidney peritubular capillaries are particularly susceptible to injury, resulting in dysregulated angiogen- esis, capillary rarefaction and regression, and progressive loss of kidney function. However, little is known about the structure and function of human kidney microvasculature. Here, we isolated, purified, and characterized human kidney peritubular microvascular endothelial cells (HKMECs) and reconstituted a three-dimensional human kidney microvasculature in a flow-directed microphysiologic system. By combining epithelial cell depletion and cell culture in media with high concentrations of vascular endothelial growth factor, we obtained HKMECs of high purity in large quantity. Unlike other endothelial cells, isolated HKMECs depended on high vascular endothelial growth factor concentration for survival and growth and exhibited high tubulogenic but low angiogenic potential. Furthermore, HKMECs had a different transcriptional profile. Under flow, HKMECs formed a thin fenestrated endothelium with a functional permeability barrier. In conclusion, this three- dimensional HKMEC-specific microphysiologic system recapitulates human kidney microvascular structure and function and shows phenotypic characteristics different from those of other microvascular endothelial cells. J Am Soc Nephrol 27: 2370–2381, 2016. doi: 10.1681/ASN.2015070747 The kidneys play an essential role in the body microvessels are highly susceptible to rarefaction af- to eliminate harmful substances from blood, in- ter exposure to toxins, xenobiotics, or injury.9,10 After cluding endogenous metabolic waste products, injured, they exhibit limited regenerative capacity, exogenously administered xenobiotics, and envi- which may contribute to tissue ischemia, tubular dys- ronmental toxins. As a major recipient of cardiac function, inflammation, fibrosis, and the develop- output (approximately 25%) and the primary filter ment of CKD.11 of exogenous drugs and toxins, kidneys are highly vascular, and the tubulointerstitium is particularly Received July 8, 2015. Accepted October 29, 2015. susceptible to injury, clinically resulting in AKI1 G.L. and R.J.N. contributed equally to this work. and contributing to the incidence and progression of CKD.2,3 Present addresses: Dr. Giovanni Ligresti, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and Of the two major components in the kidney Dr. Jeremy S. Duffield, Biogen Idec, Cambridge, Massachusetts. tubulointerstitium, the kidney microvasculature has Published online ahead of print. Publication date available at received relatively less attention in human studies. www.jasn.org. These vessels play a critical role in delivering nutrients Correspondence: Dr. Jonathan Himmelfarb, 325 Ninth Avenue, to tubular epithelial cells, possess unique transport Seattle, WA 98104, or Dr. Ying Zheng, 850 Republican Street, – properties,4 7 and participate in the tubular secretion Seattle, WA 98109. Email: [email protected] or yingzy@ and reabsorption of solutes.8 Studies over the past uw.edu decade have shown that kidney peritubular Copyright © 2016 by the American Society of Nephrology 2370 ISSN : 1046-6673/2708-2370 JAmSocNephrol27: 2370–2381, 2016 www.jasn.org BASIC RESEARCH The mechanisms underlying the microvascular response to fetal kidneys at that stage contained established nephrons, peritubular kidney injury, however, remain unclear, in part including glomeruli, tubules, and interstitium (Figure 1A), and because of difficulties resulting from in vivo imaging as well as have begun to produce urine. Compared with the mature adult challenges in isolating human kidney microvascular cells for in kidneys (Figure 1B), fetal kidneys showed signs of ongoing vitro study.12 Although glomerular endothelial cells have been development, exemplified by having a higher cellularity successfully isolated and characterized,13,14 little progress has [(1.6660.04)3106 cells per mm3 in fetal versus (0.6160.08) been made on human kidney peritubular microvascular cells. 3106 cells per mm3 in adults] and smaller glomeruli diameter Much of our understanding of kidney capillary formation and (73.75617.5 mm in fetal versus 166.25622.5 mm in the adult). maintenance has been extrapolated from the study of other en- In the interstitium of fetal kidneys, the microvasculature has dothelial cells,9,15 which may not capture specific properties of established a network around the tubules, and endothelial cells the human kidney peritubular microvasculature. New evidence strongly express CD31 (Figure 1A.2). The adult kidneys have from genetic fate–mapping studies in mice suggests that the fully established tubular structure surrounded with a robust microvascular endothelium of the internal organs may not arise peritubular microvascular network that strongly expresses from a single–yolk sac progenitor as was originally thought but CD31 (Figure 1B.2), VE Cadherin, and CD34 (Supplemental rather, from discrete organ–specific mesenchymal cells that ap- Figure 1, A and B). This peritubular microvascular endothe- pear early in embryogenesis and subsequently, give rise to mul- lium is enveloped by a scattered layer of PDGFRb+ stroma tiple organ–specific populations, including the endothelium.16 (Supplemental Figure 1, C and D). In addition, the peritubular Odd Skipped–Related 1–positive progenitors likely give rise to microvascular endothelium was distinguished from the glo- all cell populations in the kidney, including the microvascular merular endothelium by low granular expression of vWF and endothelium. This suggests that, rather than the endothelium high expression of a plasmalemma protein (PV1) delineating being imposed on by the organ developing around it, organ- fenestral diaphragms (Figure 1, A.3 and B.3). In adult kidneys, specific characteristics might be intrinsic to the endothelium.17 glomerular endothelium did not express PV1, whereas partial Another important characteristic of the kidney microvascu- staining of PV1 was still present in the fetal kidney glomeruli, lature istheconstantsubjectionto highblood flow andtransport. suggesting the development stage of the fetal kidneys with im- Conventional planar cultures of endothelial cells fail to recreate mature glomerular capillaries. This is consistent with previous the in vivo physiology of the microvasculature with respect to the observations that PV1 is present in the glomerular capillaries three-dimensional (3D) geometry (lumen and axial branching) during early development but no longer expressed in postnatal and the interactions of the endothelium with blood flow and glomerular endothelium.19 extracellular matrix. To address these challenges, we have re- The endothelial cell population (CD31+CD452) in human cently engineered functional vascular networks on the basis of kidneys was identified with flow cytometric analysis and microfluidic design principles that permit precise control of accounted for 3.161.5% of cells in fetal kidney tissues (Figure vascular cell types, branching architecture, lumen diameter, 1C) and 2.262.1% of cells in adults (Figure 1D). The direct and flow dynamics.18 This approach allows us to now recon- sorting of this population from flow cytometry, however, struct human kidney microvessels under physiologic geometry resulted in limited cell survival, lack of attachment, and and flow conditions. impurity when cultured. Our modified enrichment protocol In this study, we present new methods to isolate, purify, and (Figure 2A) showed that depletion of epithelial cells and supple- expand human kidney peritubular microvascular endothelial cells menting with a high concentration of vascular endothelial (HKMECs) and recreate the kidney microvasculature with growth factor (VEGF) in culture media were critical for enhanc- appropriate geometry and flow. We show that HKMEC-formed ing endothelial cell growth (Figure 2B) and achieving purified microvessels have kidney-specific properties, exemplified by the HKMECs (VE Cadherin+/CD31+ CD452 PDGFRb2)inlarge presence of fenestral diaphragms on the endothelial membrane, quantities. low angiogenic potential, and increased sensitivity to flow-induced Isolated HKMECs showed expression of typical endothelial biophysical changes. These experiments indicate a functioning transcripts by RT-PCR, and expressed genes include PECAM, human kidney microvasculature can be recapitulated in vitro. VE Cadherin, VEGFR2, TIE2, vWF,andPDGF-BB as well as We discuss the potential application of our system for modeling genes restricted to microvascular ECs, including ROBO4 and nephrotoxicity as well as the onset and progression of kidney CD146 (Figure 2C, Supplemental Table 1). The purity was also disease. verified by showing that these cells lack CD45 and E Cadherin expression. Isolated HKMECs from both fetal and adult tissue formed sheets in two-dimensional (2D) culture (Figure 2, D RESULTS and E) with consistent expression of CD31 (Figure 2, D.1
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