Christof Westenfelder

Christof Westenfelder
University of Utah | UOU · Departments of Mecicine and Physiology

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157
Publications
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Publications

Publications (157)
Article
We published that treatment with allogeneic, species specific NIs, organoids of Mesenchymal Stromal Cells (MSCs) and culture expanded islet cells (ICs) functionally cured/improved the diabetic state in NOD mice, insulin dependent pet dogs, and NOD/SCID mice treated with dog or human NIs without requiring antirejection drugs or encapsulation devices...
Article
Initial reports from Clinical Trials with cell-based interventions for the urgently needed therapy of T1DM show: (1) An open, s.c.-placed encapsulation device containing insulin-producing progenitor cells that require anti-rejection drugs has failed to adequately improve glycemic control. (2) The i.v. administration of stem cell-derived insulin-pro...
Article
Full-text available
Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of...
Article
The scarcity of suitable pancreas/islet donors, the life-long need for potentially toxic anti-rejection drugs for transplants and certain biotherapies, and failure of some immune-isolating encapsulation devices collectively warrant the urgent development of novel therapies for T1DM that significantly expand the donor pool without reliance on anti-r...
Article
Full-text available
Introduction Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing CO...
Article
We reported that the i.p. administration of allogeneic Neo-Islets (NIs; 3D aggregates of allogeneic, culture-expanded Islet cells (ICs) with immune- and cyto-protective Mesenchymal Stromal Cells (MSCs)), durably restores normoglycemia in autoimmune type-1 diabetic NOD mice through omental engraftment. Similarly, our ongoing, FDA-guided pilot study...
Article
We reported that allogeneic “Neo-Islets” (NIs), organoids composed of ~ equal numbers of Mesenchymal Stromal Cells and culture expanded Islet Cells (ICs) do, when given i.p., omentally engraft and permanently restore euglycemia in auto-immune diabetic NOD mice, i.e., without the use of either encapsulation devices or antirejection drugs. Similarly,...
Article
Full-text available
We previously reported that allogeneic, intraperitoneally administered “Neo-Islets,” composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of regulatory T-cells,...
Preprint
Full-text available
We previously reported that allogeneic, intraperitoneally administered “Neo-Islets,” composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of Regulatory T-cells,...
Conference Paper
We demonstrated that ip administration of “Neo-Islets” (NIs; co-aggregation of allogeneic, culture-expanded Islet cells (ICs) with Adipose derived Stem Cells (ASCs)), resulted in their omental engraftment in immune-competent, diabetic NOD mice. This achieved durable euglyciemia without immunosuppression, and with physiologic delivery of insulin and...
Article
Full-text available
Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the s...
Article
Full-text available
Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, anti-apoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In this study, we aimed to establish a fusion protocol of bone marrow−derived human MSCs with the rat b...
Article
Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions. In this study, we compared the renoprotective, hemodynamic, and hematolog...
Article
Full-text available
Acute kidney injury (AKI) is a common clinical entity associated with high morbidity and mortality and clinical costs. The pathophysiology is multifaceted and involves inflammation, tubular injury, and vascular damage. Recently identified components include necroptosis, a special form of cell death, and autophagy. Most of the pathophysiological kno...
Article
CKD is a progressive disorder that results in ESRD, requiring chronic hemodialysis or a kidney transplant, and affects 400 million individuals globally and 36 million individuals in the United States.1 In up to 50% of all cases, CKD is caused by diabetic nephropathy (DN).2,3 CKD per se and its associated and progressive cardiovascular comorbidities...
Chapter
Full-text available
Acute kidney injury (AKI), the abrupt loss of renal function that results from ischemia, sepsis, or nephrotoxin-induced damage to vascular and tubular structures, is characterized by inflammatory processes, cellular apoptosis, and necrosis. Patient mortality remains high and treatment is largely supportive. Even mild AKI can lead to chronic kidney...
Conference Paper
Full-text available
Excellent detection of MSCSPIO was achieved in-vitro and in-vivo. In-vitro MRI revealed an linear reduction of SNR and T2* depending on concentrations of MSCSPIO (R2*∼n MSC(SPIO), (R2=0.98)). In-vivo MSCSPIO administration resulted in a SNR decrease (35±15%) and R2* increase (101±18%) in kidneys caused by MSCSPIO accumulation in contrast to SPIO or...
Patent
Full-text available
Methods described include methods of treating T1DM, the method comprising delivering a therapeutic amount of β-MSC to a subject in need thereof. Further disclosed are fusion cells comprising and MSC and a second cell wherein the nuclei of the MSC and the second cell are not fused in the fusion cell.
Conference Paper
PURPOSE The aim of the study was to develop new MRI methods for a qualitative and quantitative in-vivo tracking of SPIO-labeled MSC in rats with acute kidney injury (AKI). METHOD AND MATERIALS In-vitro MRI and R2* measurements of different concentrations (103-106 cells/ml) of SPIO(Ferucarbotran)- and unlabeled MSC in gelatin phantoms was performed...
Article
Acute kidney injury (AKI) is a common clinical entity with high morbidity and mortality rates and ever increasing medical costs. A large number of patients who are hospitalized with morbidities such as diabetes, vascular disease, or chronic kidney disease are at high risk to develop AKI due to ischemic and nephrotoxic insults. The pathophysiology o...
Chapter
Kidney ischemia reperfusion injury is a major cause of morbidity in native kidneys. Ischemia reperfusion-induced acute kidney injury (AKI) is characterized by early, alloantigen-independent inflammation. Major components of the innate immune system are activated and participate in the pathogenesis of acute kidney injury. Soluble bioactive factors i...
Article
Because pharmacological interventions for the treatment of acute kidney injury (AKI) have remained ineffective, cell-based therapies have been developed. Marrow stromal cells have been found to be safe and potentially effective in study subjects. Jung et al. demonstrate that macrophages made to overexpress anti-inflammatory interleukin-10 protect r...
Article
Full-text available
Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthca...
Article
Full-text available
AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiologi...
Article
Full-text available
AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are cu...
Article
Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their ad...
Article
Both the homing of hematopoietic stem cells (HSCs) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal-derived factor-1 (SDF-1) or CXCL12, which activates CXCR4, its cognate receptor on HSCs. We showed that the recruitment and temporary attachment of CXCR4-expressing cell...
Article
Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs a...
Article
Novel urinary biomarkers for the early, sensitive, and specific diagnosis of acute kidney injury (AKI) show promise for the improved management of patients with this treatment-resistant complication. Several biomarkers (Kim-1, lipocalin-2, osteopontin, gluthathione S-transferases) that were tested by Rouse et al. during gentamicin-induced AKI and i...
Article
Full-text available
An extensive body of preclinical and clinical data has shown that administration of adult multipotent marrow stromal cells (MSCs) effectively ameliorates experimental and clinical conditions of many different organ systems. Differentiation into organ parenchymal cells, however, is very rare, and the main mechanism for organ protection and regenerat...
Chapter
Acute renal failure (ARF) due to acute kidney injury (AKI) is defined as the abrupt partial or complete loss of kidney functions that results in disturbed volume, electrolyte and acid-base balance, and uremic, multisystem complications due to retention of toxic waste products, a heightened inflammatory state, and generation of reactive oxygen speci...
Article
Acute kidney injury (AKI) is a common clinical complication, associated with poor outcomes and the development of chronic kidney disease. Despite major advances in the understanding of its pathophysiology, available therapies for AKI are only supportive; therefore, adequate functional recovery from AKI must predominantly rely on the kidney's own re...
Article
We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury...
Article
New discoveries and developments in the biology and propagation of stem cells have fueled a whole new field of Medicine that has sparked great interest in the scientific community as well as in the general media and public. Stem cells are a very prominent and debated topic and have given ground to a new field of therapy in Medicine, which is called...
Article
Adult stem cell treatment of complex disorders is a promising therapeutic approach and multipotent marrow stromal cells (MSCs) have been shown to be effective in various animal models of diseases. Acute kidney injury (AKI) is a common and serious problem in hospitalized patients and bone marrow derived multipotent MSCs have been shown to be effecti...
Article
Effective and targeted delivery of cells to injured organs is critical to the development of cell therapies. However, currently available in vivo cell tracking methods still lack sufficient sensitivity and specificity. We examined, therefore, whether a highly sensitive and specific bioluminescence method is suitable to noninvasively image the organ...
Article
Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality. Likely due to its complex pathophysiology, therapies with a single pharmacological agent have generally failed to improve outcomes. In contrast, stem cell-based interventions utilize these cells' ability to simultaneously target multiple pathophysiol...
Chapter
Novel therapies for the treatment of heart and kidney diseases are urgently needed. Because bone marrow derived cells have shown tremendous promise we utilized common animal models for myocardial infarction (MI) and acute kidney injury (AKI) to test the potential of mesenchymal stem cells (MSC) as a tool for organ regeneration. Cell tracking was ac...
Article
Full-text available
Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow de...
Article
Full-text available
Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in pat...
Article
Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. There are in general two types of stem cells, embryonic and adult stem cells. While embryonic stem cell therapy has been riddled with problems of allogeneic rejection and ethical concerns, adult stem cells have long been used in the treatme...
Article
Introduction: The aim of regenerative medicine is the reconstitution of the physiological structure of critically damaged organs. Bone marrow derived stem cells (BMDCs) show promising therapeutic potential. BMDCs are already used in oncology and are ideally suited for regenerative medicine due to their regenerative potential and safety profile. Met...
Article
To evaluate MRI for a qualitative and quantitative in vivo tracking of intraaortal injected iron oxide-labeled mesenchymal stem cells (MSC) into rats with acute kidney injury (AKI). In vitro MRI and R2* measurement of nonlabeled and superparamagnetic iron oxide (SPIO)-labeled MSC (MSC(SPIO)) was performed in correlation to cellular iron content and...
Article
Acute kidney injury (AKI) is a major clinical problem in which a critical vascular, pathophysiological component is recognized. We demonstrated previously that mesenchymal stem cells (MSC), unlike fibroblasts, are significantly renoprotective after ischemia-reperfusion injury and concluded that this renoprotection is mediated primarily by paracrine...
Article
Erythropoietin (EPO), a 34-kDa glycoprotein, is produced predominantly by peritubular interstitial cells (PIC) in the renal cortex and is physiologically released when ambient oxygen pressure falls. However, the exact nature of EPO-producing cells in the kidney is not well understood. We discovered that brief administration of a low-molecular-weigh...
Article
Acute kidney injury (AKI) secondary to ischemia continues to be a major clinical problem due to its high morbidity and mortality, and limited treatment options. Animal models are critical to both the study of the pathophysiology of AKI and the development of new interventions. Although histological changes at the glomerulotubular junction have been...
Article
Full-text available
Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EPO) in some organs (e.g., the brain) is higher than...
Article
Since acute renal failure (ARF) remains a common clinical syndrome with high mortality rates and limited treatment options, fundamentally new interventions are needed. We reported recently (Am J Physiol and Kidney Int 2005) that the infusion of mesenchymal stem cells (MSCs) is strikingly renoprotective in rats with severe ischemic ARF. Because esse...
Article
Adult stem cells are promising for the development of novel therapies in regenerative medicine. Acute renal failure (ARF) remains a frequent clinical complication, associated with an unacceptably high mortality rate, in large part due to the ineffectiveness of currently available therapies. The aim of this study was, therefore, to evaluate the ther...
Article
Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome...
Article
Stem cell and leukocyte migration during homeostasis and inflammation is regulated by a number of chemokines. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are important mediators of leukocyte homeostasis. The postischemic kidney has been shown to recruit different leukocyte populations, including bone marrow-derived stem cells. Ther...
Article
The chemokine stromal cll-derived factor-1 (SDF-1) and its receptor CXCR4, expressed by hematopoietic stem cells (HSC) and other cells, represents a major mediator-system for G-CSF-induced hematopoietic stem cell (HSC) mobilization and stem cell (SC) homing to the bone marrow (BM) after BM transplantation. HSC have been shown to contribute to repai...
Article
Acute renal failure (ARF), resulting from ischemic or toxic insults, remains a major health care problem because of its grave prognosis and the limited effectiveness of available treatment modalities. On the basis of the recent demonstration that hematopoietic stem cells can differentiate into renal cells and the authors' observation here that ARF...