http://stemcellres.com The most accessed research articles published by Stem Cell Research & Therapy 2012-01-17T00:00:00Z IntroductionThe induced pluripotent stem cell (iPSC) technology allows generation of patient-specific pluripotent stem cells, thereby providing a novel cell-therapy platform for severe degenerative diseases. One of the key issues for clinical-grade iPSC derivation is the accessibility of donor cells used for reprogramming. Methods: We examined the feasibility of reprogramming mobilized GMP-grade hematopoietic progenitor cells (HPCs) and peripheral blood mononuclear cells (PBMCs) and tested the pluripotency of derived iPS clones. Results: Ectopic expression of OCT4, SOX2, KLF4, and c-MYC in HPCs and PBMCs resulted in rapid iPSC derivation. Long-term time-lapse imaging revealed efficient iPSC growth under serum- and feeder-free conditions with frequent mitotic events. HPC- and PBMC-derived iPS cells expressed pluripotency-associated markers, including SSEA-4, TRA-1-60, and NANOG. The global gene-expression profiles demonstrated the induction of endogenous pluripotent genes, such as LIN28, TERT, DPPA4, and PODXL, in derived iPSCs. iPSC clones from blood and other cell sources showed similar ultrastructural morphologies and genome-wide gene-expression profiles. On spontaneous and guided differentiation, HPC- and PBMC-derived iPSCs were differentiated into cells of three germ layers, including insulin-producing cells through endodermal lineage, verifying the pluripotency of the blood-derived iPSC clones. Conclusions: Because the use of blood cells allows minimally invasive tissue procurement under GMP conditions and rapid cellular reprogramming, mobilized HPCs and unmobilized PBMCs would be ideal somatic cell sources for clinical-grade iPSC derivation, especially from diabetes patients complicated by slow-healing wounds. http://stemcellres.com/content/2/6/46 Seiga Ohmine Allan Dietz Michael Deeds Katherine Hartjes David Miller Tayaramma Thatava Toshie Sakuma Yogish Kudva Yasuhiro Ikeda Stem Cell Research & Therapy 2011, null:46 2011-11-16T00:00:00Z doi:10.1186/scrt87 iPSCs from blood cells Hematopoietic progenitor cells and peripheral blood mononuclear cells could be ideal somatic cell sources for clinical-grade induced pluripotent stem cell (iPSC) derivation, allowing minimally invasive tissue procurement and rapid cellular reprogramming. /content/figures/scrt87-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 46 2011-11-16T00:00:00Z XML IntroductionEnd-stage renal disease (ESRD) is a major public health problem. Although kidney transplantation is a viable therapeutic option, this therapy is associated with significant limitations, including a shortage of donor organs. Induced pluripotent stem (iPS) cell technology, which allows derivation of patient-specific pluripotent stem cells, could provide a possible alternative modality for kidney replacement therapy for patients with ESRD. Methods: The feasibility of iPS cell generation from patients with a history of ESRD was investigated using lentiviral vectors expressing pluripotency-associated factors. Results: In the present article we report, for the first time, generation of iPS cells from kidney transplant recipients with a history of autosomal-dominant polycystic kidney disease (ADPKD), systemic lupus erythematosus, or Wilms tumor and ESRD. Lentiviral transduction of OCT4, SOX2, KLF4 and c-MYC, under feeder-free conditions, resulted in reprogramming of skin-derived keratinocytes. Keratinocyte-derived iPS cells exhibited properties of human embryonic stem cells, including morphology, growth properties, expression of pluripotency genes and surface markers, spontaneous differentiation and teratoma formation. All iPS cell clones from the ADPKD patient retained the conserved W3842X mutation in exon 41 of the PKD1 gene. Conclusions: Our results demonstrate successful iPS cell generation from patients with a history of ESRD, PKD1 gene mutation, or chronic immunosuppression. iPS cells from autosomal kidney diseases, such as ADPKD, would provide unique opportunities to study patient-specific disease pathogenesis in vitro. http://stemcellres.com/content/2/6/48 Tayaramma Thatava Adam Armstrong Josep Genebriera De Lamo Ramakrishna Edukulla Yulia Krotova Khan Toshie Sakuma Seiga Ohmine Jamie Sundsbak Peter Harris Yogish Kudva Yasuhiro Ikeda Stem Cell Research & Therapy 2011, null:48 2011-12-06T00:00:00Z doi:10.1186/scrt89 iPSCs generated after kidney transplantation Disease-specific induced pluripotent stem cells (iPSCs) have been generated from kidney transplant recipients, providing opportunities to study patient-specific disease pathogenesis in vitro and demonstrating potential for autologous kidney replacement therapy. /content/figures/scrt89-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 48 2011-12-06T00:00:00Z XML For many years, the hematopoietic stem cell (HSC) has been well characterized in mice as a cell that can singly reconstitute the whole hematopoietic system of primary recipient animals as well as that of secondary hosts. That clinical bone marrow transplantation is a successful treatment strategy is indirect evidence that such a cell exists in humans. To date, similar criteria have not been applied to human HSCs. However, using a humanized mouse model of xenotransplantation, a recent paper shows that single human cells can fully reconstitute the lymphomyeloid system of primary recipient animals and, in some cases, that of secondary hosts. http://stemcellres.com/content/3/1/1 Rhodri Ceredig Stem Cell Research & Therapy 2012, null:1 2012-01-13T00:00:00Z doi:10.1186/scrt92 Identifying human hematopoietic stem cells Rhodri Ceredig discusses a significant advance in our understanding of human hematopoiesis. /content/figures/scrt92-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 1 2012-01-13T00:00:00Z XML Stem cell transplantation is emerging as a potential therapy to treat heart diseases. Promising results from early animal studies led to an explosion of small, non-controlled clinical trials that created even further excitement by showing that stem cell transplantation improved left ventricular systolic function and enhanced remodelling. However, the specific mechanisms by which these cells improve heart function remain largely unknown. A large variety of cell types have been considered to possess the regenerative ability needed to repair the damaged heart. One of the most studied cell types is the bone marrow-derived mononuclear cells and these form the focus of this review. This review article aims to provide an overview of their use in the setting of acute myocardial infarction, the challenges it faces and the future of stem cell therapy in heart disease. http://stemcellres.com/content/3/1/2 Samer Arnous Abdul Mozid John Martin Anthony Mathur Stem Cell Research & Therapy 2012, null:2 2012-01-17T00:00:00Z doi:10.1186/scrt93 Stem cell therapy in heart disease The use of bone-marrow derived mononuclear cells in cardiac repair after acute myocardial infarction, a leading cause of death and disability, is reviewed by Anthony Mathur and colleagues. /content/figures/scrt93-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 2 2012-01-17T00:00:00Z XML IntroductionMesenchymal stem cells (MSCs) play a central role in mediating endogenous repair of cell and tissue damage. Biological aging is a universal process that results in changes at the cellular and molecular levels. In the present study, the role of microRNA (miRNA) in age-induced molecular changes in MSCs derived from adipose tissue (ASCs) and bone marrow (BMSCs) from young and old human donors were investigated using an unbiased genome-wide approach. Methods: Human ASCs and BMSCs from young and old donors were cultured and total RNA was isolated. The miRNA fraction was enriched and used to determine the expression profile of miRNA in young and old donor MSCs. Based on miRNA expression, differences in donor MSCs were further investigate utilizing differentiation assays, Western blot, immunocytochemistry, and bioinformatics. Results: Biological aging demonstrated reduced osteogenic and adipogenic potential in ASCs isolated from older donors, while cell size, complexity and cell surface markers remained intact with aging. Analysis of miRNA profiles revealed that small subsets of active miRNAs changed secondary to aging. Evaluation of miRNA showed significantly decreased levels of gene expression of inhibitory kappa B kinase (IkappaB), interleukin-1alpha, inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase/p38, ERK1/2, c-fos, and c-jun in MSCs from older donors by both bioinformatics and Western blot analysis. Nuclear factor kappa B (NF-kappaB), myc, and interleukin-4 receptor mRNA levels were significantly elevated in aged cells from both the adipose and bone marrow depots. Immunocytochemistry showed nuclear localization in young donors, however, a cytosolic predominance of phosphorylated NF-kappaB in ASCs from older donors. Western blot demonstrated significantly elevated levels of NF-kappaB subunits, p65 and p50, and AKT. Conclusions: These findings suggest that differential expression of miRNA is an integral component of biological aging in MSCs. http://stemcellres.com/content/2/6/49 Amitabh Pandey Julie Semon Deepak Kaushal Regina O'Sullivan Julie Glowacki Jeffery Gimble Bruce Bunnell Stem Cell Research & Therapy 2011, null:49 2011-12-14T00:00:00Z doi:10.1186/scrt90 MicroRNAs in stem cell aging Differential expression of microRNAs is an integral component of biological aging in mesenchymal stem cells, regulating gene expression related to a variety of functions including cellular proliferation and inflammation. /content/figures/scrt90-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 49 2011-12-14T00:00:00Z PDF Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that are isolated from many adult tissues, in particular from the bone marrow and adipose tissue. Along with their capacity for differentiating into cells of mesodermal lineage, such as adipocytes, osteoblasts and chondrocytes, these cells have also generated great interest for their ability to display immunomodulatory capacities. Indeed, a major breakthrough came with the finding that they are able to induce peripheral tolerance, suggesting they may be used as therapeutic tools in immune-mediated disorders. The present review aims at discussing the current knowledge on the targets and mechanisms of MSC-mediated immunosuppression as well as the potential use of MSCs as modulators of immune responses in a variety of diseases related to alloreactive immunity or autoimmunity http://stemcellres.com/content/1/1/2 Soufiane Ghannam Carine Bouffi Farida Djouad Christian Jorgensen Daniele Noel Stem Cell Research & Therapy 2010, null:2 2010-03-15T00:00:00Z doi:10.1186/scrt2 Immunosuppression by mesenchymal stem cells Ghannam et al discuss the targets and mechanisms of mesenchymal stem cell (MSC)-mediated immunosuppression, and the potential use of MSCs to modulate immune responses in a variety of autoimmune diseases. /content/figures/scrt2-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 2 2010-03-15T00:00:00Z XML Distinct stem cell types have been established from embryos and identified in the fetal tissues and umbilical cord blood as well as in specific niches in many adult mammalian tissues and organs such as bone marrow, brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, and prostate. All stem cells are undifferentiated cells that exhibit unlimited self-renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishing the cells or to tissue regeneration after injury. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of stem cells in the treatment of ophthalmic disorders. Experimental and human studies with intravitreal bone marrow-derived stem cells have begun. This paper reviews recent advances and potential sources of stem cells for cell therapy in retinal diseases. http://stemcellres.com/content/2/6/50 Rubens Siqueira Stem Cell Research & Therapy 2011, null:50 2011-12-29T00:00:00Z doi:10.1186/scrt91 /content/figures/scrt91-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 50 2011-12-29T00:00:00Z XML IntroductionStem cell transplantation is a promising therapeutic strategy for the treatment of stroke. Mesenchymal stem cells (MSCs) are a potential cell source for clinical application because they can be easily obtained and cultivated with a high proliferative capacity. The safety and efficacy of cell therapy depends on the mode of cell administration. To determine the therapeutic potential of intrathecal administration of MSCs by lumbar puncture (LP), we administrated human umbilical cord blood-derived MSCs (hUCB-MSCs) intrathecally into the lumbar spinal cord or intravenously into the tail vein in a rat model of stroke, and then investigated whether hUCB-MSCs could enter the brain, survive, and improve post-stroke neurological functional recovery. Methods: hUCB-MSCs (1.0 × 106) were administrated three days after stroke induced by occlusion of the middle cerebral artery. The presence of hUCB-MSCs and their survival and differentiation in the brain tissue of the rats was examined by immunohistochemistry. Recovery of coordination of movement after administration of hUCB-MSCs was examined using a Rotarod test and adhesive-removal test on the 7th, 14th, 21st, and 28th days after ischemia. The volume of ischemic lesions seven days after the experimental procedure was evaluated using 2-3-5-triphenyltetrazolium (TTC) staining. Results: Rats receiving hUCB-MSCs intrathecally by LP had a significantly higher number of migrated cells within the ischemic area when compared with animals receiving cells intravenously. In addition, many of the cells administered intrathecally survived and a subset of them expressed mature neural-lineage markers, including the mature neuron marker NeuN and glial fibrillary acidic protein, typical of astrocytes. Animals that received hUCB-MSCs had significantly improved motor function and reduced ischemic damage when compared with untreated control animals. Regardless of the administration route, the group treated with 1 × 106 hUCB-MSCs showed better neurological recovery, without significant differences between the two treatment groups. Importantly, intrathecal administration of 5 × 105 hUCB-MSCs significantly reduced ischemic damage, but not in the intravenously treated group. Furthermore, the cells administered intrathecally survived and migrated into the ischemic area more extensively, and differentiated significantly into neurons and astrocytes. Conclusions: Together, these results indicate that intrathecal administration of MSCs by LP may be useful and feasible for MSCs treatment of brain injuries, such as stroke, or neurodegenerative disorders. http://stemcellres.com/content/2/5/38 Jung Yeon Lim Chang Hyun Jeong Jin Ae Jun Seong Muk Kim Chung Heon Ryu Yun Hou Wonil Oh Jong Wook Chang Sin-Soo Jeun Stem Cell Research & Therapy 2011, null:38 2011-09-22T00:00:00Z doi:10.1186/scrt79 Intrathecal administration of stem cells in stroke Mesenchymal stem cells administered intrathecally by lumbar puncture significantly reduced ischemic damage in a stroke-affected rat model, demonstrating the potential of this delivery method in the treatment of brain injuries or neurodegenerative disorders. /content/figures/scrt79-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 38 2011-09-22T00:00:00Z XML Treatment of extensive bone defects requires autologous bone grafting or implantation of bone substitute materials. An attractive alternative has been to engineer fully viable, biological bone grafts in vitro by culturing osteogenic cells within three-dimensional scaffolds, under conditions supporting bone formation. Such grafts could be used for implantation, but also as physiologically relevant models in basic and translational studies of bone development, disease and drug discovery. A source of human cells that can be derived in large numbers from a small initial harvest and predictably differentiated into bone forming cells is critically important for engineering human bone grafts. We discuss the characteristics and limitations of various types of human embryonic and adult stem cells, and their utility for bone tissue engineering. http://stemcellres.com/content/1/2/10 Darja Marolt Miomir Knezevic Gordana Vunjak-Novakovic Stem Cell Research & Therapy 2010, null:10 2010-05-04T00:00:00Z doi:10.1186/scrt10 Treating bone defects with stem cells Using human stem cells for bone tissue engineering may be a viable alternative to treating bone defects with autologous bone grafting or implanting bone substitute materials. /content/figures/scrt10-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 10 2010-05-04T00:00:00Z XML IntroductionHuman multipotent mesenchymal stem cell (MSC) therapies are being tested clinically for a variety of disorders, including Crohn's disease, multiple sclerosis, graft-versus-host disease, type 1 diabetes, bone fractures, and cartilage defects. However, despite the remarkable clinical advancements in this field, most applications still use traditional culture media containing fetal bovine serum. The ill-defined and highly variable nature of traditional culture media remains a challenge, hampering both the basic and clinical human MSC research fields. To date, no reliable serum-free medium for human MSCs has been available. Methods: In this study, we developed and tested a serum-free growth medium on human bone marrow-derived MSCs through the investigation of multiple parameters including primary cell isolation, multipassage expansion, mesoderm differentiation, cellular phenotype, and gene-expression analysis. Results: Similar to that achieved with traditional culture medium, human MSCs expanded in serum-free medium supplemented with recombinant human platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-β1 showed extensive propagation with retained phenotypic, differentiation, and colony-forming unit potential. To monitor global gene expression, the transcriptomes of bone marrow-derived MSCs expanded under serum-free and serum-containing conditions were compared, revealing similar expression profiles. In addition, the described serum-free culture medium supported the isolation of human MSCs from primary human marrow aspirate with continual propagation. Conclusions: Although the described serum-free MSC culture medium is not free of xenogeneic components, this medium provides a substitute for serum-containing medium for research applications, setting the stage for future clinical applications. http://stemcellres.com/content/1/1/8 Lucas Chase Uma Lakshmipathy Luis Solchaga Mahendra Rao Mohan Vemuri Stem Cell Research & Therapy 2010, null:8 2010-04-02T00:00:00Z doi:10.1186/scrt8 New serum-free medium for stem cell expansion A novel serum-free mesenchymal stem cell culture medium could substitute ill-defined traditional culture medium for research applications – an important step in the development of a more clinically relevant culture system. /content/figures/scrt8-toc.gif Stem Cell Research & Therapy 1757-6512 ${item.volume} 8 2010-04-02T00:00:00Z XML