Stefan M. Kren

Bio: Stefan M. Kren is an academic researcher from University of Minnesota. The author has contributed to research in topics: Decellularization & Kidney. The author has an hindex of 21, co-authored 37 publications receiving 4364 citations.

Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart

Abstract: About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.

Role of aldosterone in the remnant kidney model in the rat

Abstract: The renin-angiotensin-aldosterone system (RAAS) participates in the injury sustained by the remnant kidney. Our studies assessed the importance of aldosterone in that model and the response of aldosterone to drugs interfering with the RAAS. Initially, four groups of rats were studied: SHAM-operated rats, untreated remnant rats (REM), REM rats treated with losartan and enalapril (REM AIIA), and REM AIIA rats infused with exogenous aldosterone (REM AIIA + ALDO). The last group was maintained with aldosterone levels comparable to those in untreated REM rats by constant infusion of exogenous aldosterone. REM rats had larger adrenal glands and a > 10-fold elevation in plasma aldosterone compared to SHAM. REM AIIA rats demonstrated significant suppression of the hyperaldosteronism as well as marked attenuation of proteinuria, hypertension, and glomerulosclerosis compared to REM. REM AIIA + ALDO rats manifested greater proteinuria, hypertension, and glomerulosclerosis than REM AIIA rats. Indeed, by 4 wk of observation all of these features of the experimental disease were similar in magnitude in REM AIIA + ALDO and untreated REM. In separate REM rats spironolactone administration did not reduce glomerular sclerosis but did transiently reduce proteinuria, lowered arterial pressure, and lessened cardiac hypertrophy. In summary, aldosterone contributes to hypertension and renal injury in the remnant kidney model.

Isolation and Characterization of Kidney-Derived Stem Cells

Abstract: Acute kidney injury is followed by regeneration of damaged renal tubular epithelial cells. The purpose of this study was to test the hypothesis that renal stem cells exist in the adult kidney and participate in the repair process. A unique population of cells that behave in a manner that is consistent with a renal stem cell were isolated from rat kidneys and were termed multipotent renal progenitor cells (MRPC). Features of these cells include spindle-shaped morphology; self-renewal for >200 population doublings without evidence for senescence; normal karyotype and DNA analysis; and expression of vimentin, CD90 (thy1.1), Pax-2, and Oct4 but not cytokeratin, MHC class I or II, or other markers of more differentiated cells. MRPC exhibit plasticity that is demonstrated by the ability of the cells to be induced to express endothelial, hepatocyte, and neural markers by reverse transcriptase-PCR and immunohistochemistry. The cells can differentiate into renal tubules when injected under the capsule of an uninjured kidney or intra-arterially after renal ischemia-reperfusion injury. Oct4 expression was seen in some tubular cells in the adult kidney, suggesting these cells may be candidate renal stem cells. It is proposed that MRPC participate in the regenerative response of the kidney to acute injury.

Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction.

Abstract: Dietary protein restriction imposed before renal injury is established in the remnant kidney model in the rat reduces glomerular hypertension and hyperperfusion and renal injury. We demonstrate that dietary protein restriction (6% vs. 20%) imposed on a background of established renal injury in the remnant model leads to a greater preservation of renal function as measured by glomerular filtration rate and fractional clearances of albumin and IgG, despite the persistence of systemic hypertension. In similarly prepared rats, dietary protein restriction (6% vs. 20%) led to a lower glomerular capillary hydraulic pressure, a higher ultrafiltration coefficient, and similar single nephron filtration rates. In addition, less impairment of glomerular permselectivity was demonstrable after protein restriction. Our data demonstrate that the preservation of renal function with dietary protein restriction after established glomerular injury follows upon reduction of glomerular capillary hydraulic pressure, despite constancy of single nephron filtration rate and plasma flow and persistence of arterial hypertension.

3D bioprinting of tissues and organs

Abstract: Additive manufacturing, otherwise known as three-dimensional (3D) printing, is driving major innovations in many areas, such as engineering, manufacturing, art, education and medicine. Recent advances have enabled 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities requires the integration of technologies from the fields of engineering, biomaterials science, cell biology, physics and medicine. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery and toxicology.

Image Processing

Abstract: MUCKE aims to mine a large volume of images, to structure them conceptually and to use this conceptual structuring in order to improve large-scale image retrieval. The last decade witnessed important progress concerning low-level image representations. However, there are a number problems which need to be solved in order to unleash the full potential of image mining in applications. The central problem with low-level representations is the mismatch between them and the human interpretation of image content. This problem can be instantiated, for instance, by the incapability of existing descriptors to capture spatial relationships between the concepts represented or by their incapability to convey an explanation of why two images are similar in a content-based image retrieval framework. We start by assessing existing local descriptors for image classification and by proposing to use co-occurrence matrices to better capture spatial relationships in images. The main focus in MUCKE is on cleaning large scale Web image corpora and on proposing image representations which are closer to the human interpretation of images. Consequently, we introduce methods which tackle these two problems and compare results to state of the art methods. Note: some aspects of this deliverable are withheld at this time as they are pending review. Please contact the authors for a preview.

Chronic renal failure after transplantation of a nonrenal organ.

Abstract: Background Transplantation of nonrenal organs is often complicated by chronic renal disease with multifactorial causes. We conducted a population-based cohort analysis to evaluate the incidence of chronic renal failure, risk factors for it, and the associated hazard of death in recipients of nonrenal transplants. Methods Pretransplantation and post-transplantation clinical variables and data from a registry of patients with end-stage renal disease (ESRD) were linked in order to estimate the cumulative incidence of chronic renal failure (defined as a glomerular filtration rate of 29 ml per minute per 1.73 m2 of body-surface area or less or the development of ESRD) and the associated risk of death among 69,321 persons who received nonrenal transplants in the United States between 1990 and 2000. Results During a median follow-up of 36 months, chronic renal failure developed in 11,426 patients (16.5 percent). Of these patients, 3297 (28.9 percent) required maintenance dialysis or renal transplantation. The five-year risk of chronic renal failure varied according to the type of organ transplanted - from 6.9 percent among recipients of heart-lung transplants to 21.3 percent among recipients of intestine transplants. Multivariate analysis indicated that an increased risk of chronic renal failure was associated with increasing age (relative risk per 10-year increment, 1.36; P Conclusions The five-year risk of chronic renal failure after transplantation of a nonrenal organ ranges from 7 to 21 percent, depending on the type of organ transplanted. The occurrence of chronic renal failure among patients with a nonrenal transplant is associated with an increase by a factor of more than four in the risk of death.

Complexity in biomaterials for tissue engineering

Abstract: The molecular and physical information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cell-instructive scaffolds, while others remain largely unexplored. Yet for commercial success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of production. This is spurring interest in recreating extracellular influences in simplified forms, from the reduction of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clinical and commercial pressures on tissue engineering.