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The promise of cellular therapy lies in the repair of damaged organs and tissues in vivo as well as generating tissue constructs in vitro for subsequent transplantation. Unfortunately, the lack of available donor cell sources limits its ultimate clinical applicability. Stem cells are a natural choice for cell therapy due to their pluripotent nature and self-renewal capacity. Creating reserves of undifferentiated stem cells and subsequently driving their differentiation to a lineage of choice in an efficient and scalable manner is critical for the ultimate clinical success of cellular therapeutics. In recent years, a variety of biomaterials have been incorporated in stem cell cultures, primarily to provide a conducive microenvironment for their growth and differentiation and to ultimately mimic the stem cell niche. In this review, we examine applications of natural and synthetic materials, their modifications as well as various culture conditions for maintenance and lineage-specific differentiation of embryonic and adult stem cells.
Eileen Dawsona Gazell Mapilia Kathryn Ericksona Sabia Taqvia Krishnendu RoyaEmail:kroy@mail.utexas.edu
[a]Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
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This review presents a summary of the various types of cellular therapy used to treat spinal cord injury. The inhibitory environment and loss of axonal connections after spinal cord injury pose many obstacles to regenerating the lost tissue. Cellular therapy provides a means of restoring the cells lost to the injury and could potentially promote functional recovery after such injuries. A wide range of cell types have been investigated for such uses and the advantages and disadvantages of each cell type are discussed along with the research studying each cell type. Additionally, methods of delivering cells to the injury site are evaluated. Based on the current research, suggestions are given for future investigation of cellular therapies for spinal cord regeneration.
Stephanie M. Willertha Shelly E. Sakiyama-ElbertaEmail:sakiyama@wustl.edu
[a]Department of Biomedical Engineering, Washington University in St. Louis, USA;[b]Center for Materials Innovation, Washington University in St. Louis, USA
The extracellular microenvironment plays a significant role in controlling cellular behavior. Identification of appropriate biomaterials that support cellular attachment, proliferation and, most importantly in the case of human embryonic stem cells, lineage-specific differentiation is critical for tissue engineering and cellular therapy. In addition to growth factors and morphogenetic factors known to induce lineage commitment of stem cells, a number of scaffolding materials, including synthetic and naturally-derived biomaterials, have been utilized in tissue engineering approaches to direct differentiation. This review focuses on recent emerging findings and well-characterized differentiation models of human embryonic stem cells. Additionally, we also discuss about various strategies that have been used in stem cell expansion.
Nathaniel S. Hwanga Shyni Varghesea Jennifer ElisseeffaEmail:jhe@jhu.edu
[a]Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA
OBJECTIVE: To assess physiologic responses and plasma endothelin (ET)-1 concentrations associated with abrupt cessation of nitric oxide (NO) inhalation in isoflurane-anesthetized horses. ANIMALS: 6 healthy adult Standardbreds. PROCEDURES: Horses were anesthetized with isoflurane in oxygen and placed in dorsal recumbency. Nitric oxide was pulsed into the respiratory tract for 2.5 hours, and then administration was abruptly discontinued. Just prior to commencement and at cessation of NO administration, and at intervals during a 30-minute period following cessation of NO inhalation, several variables including PaO(2), mean pulmonary artery pressure, venous admixture or pulmonary shunt fraction (Qs/Qt), and plasma ET-1 concentration were recorded or calculated. RESULTS: After cessation of NO inhalation, PaO(2) decreased slowly but significantly (172.7 +/- 29.8 mm Hg to 84.6 +/- 10.9 mm Hg) and Qs/Qt increased slowly but significantly (25 +/- 2% to 40 +/- 3%) over a 30-minute period. Mean pulmonary artery pressure increased slightly (14.0 +/- 1.3 mm Hg to 16.8 +/- 1 mm Hg) over the same time period. No change in serum ET-1 concentration was detected, and other variables did not change or underwent minor changes. CONCLUSIONS AND CLINICAL RELEVANCE: The improvement in arterial oxygenation during pulsed inhalation of NO to healthy isoflurane-anesthetized horses decreased only gradually during a 30-minute period following cessation of NO inhalation, and serum ET-1 concentration was not affected. Because a rapid rebound response did not develop, inhalation of NO might be clinically useful in the treatment of hypoxemia in healthy isoflurane-anesthetized horses.
Grubb TLHogman MEdner AFrendin JHHeinonen EMalavasi LMFrostell CGRyden AAlving KNyman GC
Riverview Animal Clinic, Uniontown, WA 99179, USA.
OBJECTIVE: To evaluate the effect of infection with bovine respiratory syncytial virus (BRSV) on clearance of inhaled antigens from the lungs of calves. ANIMALS: Eleven 6- to 8-week-old Holstein bull calves. PROCEDURES: Aerosolized (99m)technetium ((99m)Tc)-labeled diethylene triamine pentacetate (DTPA; 3 calves), commonly used to measure integrity of the pulmonary epithelium, and (99m)Tc-labeled ovalbumin (OA; 8 calves), commonly used as a prototype allergen, were used to evaluate pulmonary clearance before, during, and after experimentally induced infection with BRSV or sham inoculation with BRSV. Uptake in plasma (6 calves) and lung-efferent lymph (1 calf) was examined. RESULTS: Clearance of (99m)Tc-DTPA was significantly increased during BRSV infection; clearance of (99m)Tc-OA was decreased on day 7 after inoculation. Clearance time was correlated with severity of clinical disease, and amounts of (99m)Tc-OA in plasma and lymph were inversely correlated with clearance time. Minimum amounts of (99m)Tc-OA were detected at time points when pulmonary clearance of (99m)Tc-OA was most delayed. CONCLUSIONS AND CLINICAL RELEVANCE: BRSV caused infection of the respiratory tract with peak signs of clinical disease at 7 or 8 days after inoculation. Concurrently, there was a diminished ability to move inhaled protein antigen out of the lungs. Prolonged exposure to inhaled antigens during BRSV infection may enhance antigen presentation with consequent allergic sensitization and development of chronic inflammatory lung disease. IMPACT FOR HUMAN MEDICINE: Infection of humans with respiratory syncytial virus early after birth is associated with subsequent development of allergic asthma. Results for BRSV infection in these calves suggested a supportive mechanism for this scenario.
Gershwin LJGunther RAHornof WJLarson RF
Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Gene modification of cells prior to their transplantation, especially stem cells, enhances their survival and increases their function in cell therapy. Like the Trojan horse, the gene-modified cell has to gain entrance inside the host’s walls and survive and deliver its transgene products Using cellular, molecular and gene manipulation techniques the transplanted cell can be protected in a hostile environment from immune rejection, inflammation, hypoxia and apoptosis. Genetic engineering to modify cells involves constructing modules of functional gene sequences. They can be simple reporter genes or complex cassettes with gene switches, cell specific promoters and multiple transgenes. We discuss methods to deliver and construct gene cassettes with viral and non-viral delivery, siRNA, and conditional Cre/Lox P. We review the current uses of gene-modified stem cells in cardiovascular disease, diabetes, neurological diseases, (including Parkinson’s, Alzheimer’s and spinal cord injury repair), bone defects, hemophilia, and cancer.
M. Ian PhillipsaEmail:ian_phillips@kgi.edu Yao Liang Tanga
[a]Keck Graduate Institute, Claremont, Ca 91711, USA
OBJECTIVE: To investigate the use of a specific antibody index (AI) that relates Sarcocystis neurona-specific IgG quotient (Q(SN)) to total IgG quotient (Q(IgG)) for the detection of the anti-S neurona antibody fraction of CNS origin in CSF samples obtained from horses after intragastric administration of S neurona sporocysts. ANIMALS: 18 adult horses. PROCEDURES: 14 horses underwent intragastric inoculation (day 0) with S neurona sporocysts, and 4 horses remained unchallenged; blood and CSF samples were collected on days – 1 and 84. For purposes of another study, some challenged horses received intermittent administration of ponazuril (20 mg/kg, PO). Sarcocystis neurona-specific IgG concentrations in CSF (SN(CSF)) and plasma (SN(plasma)) were measured via a direct ELISA involving merozoite lysate antigen and reported as ELISA units (EUs; arbitrary units based on a nominal titer for undiluted immune plasma of 100,000 EUs/mL). Total IgG concentrations in CSF (IgG(CSF)) and plasma (IgG(plasma)) were quantified via a sandwich ELISA and a radial immunodiffusion assay, respectively; Q(SN), Q(IgG), and AI were calculated. RESULTS: Following sporocyst challenge, mean +/- SEM SN(CSF) and SN(plasma) increased significantly (from 8.8 +/- 1.0 EUs/mL to 270.0 +/- 112.7 EUs/mL and from 1,737 +/- 245 EUs/mL to 43,169 +/- 13,770 EUs/mL, respectively). Challenge did not affect total IgG concentration, Q(SN), Q(IgG), or AI. CONCLUSIONS AND CLINICAL RELEVANCE: S neurona-specific IgG detected in CSF samples from sporocyst-challenged horses appeared to be extraneural in origin; thus, this experimental challenge may not reliably result in CNS infection. Calculation of a specific AI may have application to the diagnosis of S neurona-associated myeloencephalitis in horses.
Heskett KAMackay RJ
Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA.
OBJECTIVE: To evaluate the effect of intermittent oral administration of ponazuril on immunoconversion against Sarcocystis neurona in horses inoculated intragastrically with S neurona sporocysts. ANIMALS: 20 healthy horses that were seronegative for S neurona-specific IgG. PROCEDURES: 5 control horses were neither inoculated with sporocysts nor treated. Other horses (5 horses/group) each received 612,500 S neurona sporocysts via nasogastric tube (day 0) and were not treated or were administered ponazuril (20 mg/kg, PO) every 7 days (beginning on day 5) or every 14 days (beginning on day 12) for 12 weeks. Blood and CSF samples were collected on day – 1 and then every 14 days after challenge for western blot assessment of immunoconversion. Clinical signs of equine protozoal myeloencephalitis (EPM) were monitored, and tissues were examined histologically after euthanasia. Results: Sera from all challenged horses yielded positive western blot results within 56 days. Immunoconversion in CSF was detected in only 2 of 5 horses that were treated weekly; all other challenged horses immunoconverted within 84 days. Weekly administration of ponazuril significantly reduced the antibody response against the S neurona 17-kd antigen in CSF. Neurologic signs consistent with EPM did not develop in any group; likewise, histologic examination of CNS tissue did not reveal protozoa or consistent degenerative or inflammatory changes. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of ponazuril every 7 days, but not every 14 days, significantly decreased intrathecal anti-S neurona antibody responses in horses inoculated with S neurona sporocysts. Protocols involving intermittent administration of ponazuril may have application in prevention of EPM.
Mackay RJTanhauser STGillis KDMayhew IGKennedy TJ
Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL 32610, USA.
OBJECTIVE: To determine whether soil concentrations of total or virulent Rhodococcus equi differed among breeding farms with and without foals with pneumonia caused by R equi. SAMPLE POPULATION: 37 farms in central Kentucky. Procedures-During January, March, and July 2006, the total concentration of R equi and concentration of virulent R equi were determined by use of quantitative bacteriologic culture and a colony immunoblot technique, respectively, in soil specimens obtained from farms. Differences in concentrations and proportion of virulent isolates within and among time points were compared among farms. RESULTS: Soil concentrations of total or virulent R equi did not vary among farms at any time point. Virulent R equi were identified in soil samples from all farms. Greater density of mares and foals was significantly associated with farms having foals with pneumonia attributable to R equi. Among farms with affected foals, there was a significant association of increased incidence of pneumonia attributable to R equi with an increase in the proportion of virulent bacteria between samples collected in March and July. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that virulent R equi were commonly recovered from soil of horse breeding farms in central Kentucky, regardless of the status of foals with pneumonia attributable to R equi on each farm. The incidence of foals with pneumonia attributable to R equi can be expected to be higher at farms with a greater density of mares and foals.
Cohen NDCarter CNScott HMChaffin MKSmith JLGrimm MBKuskie KRTakai SMartens RJ
Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Protection of transplanted cells from the host immune system using immunoisolation technology will be important in realizing the full potential of cell-based therapeutics. Microencapsulation of cells and cell aggregates has been the most widely explored immunoisolation strategy, but widespread clinical application of this technology has been limited, in part, by inadequate transport of nutrients, deleterious innate inflammatory responses, and immune recognition of encapsulated cells via indirect antigen presentation pathways. To reduce mass transport limitations and decrease void volume, recent efforts have focused on developing conformal coatings of micron and submicron scale on individual cells or cell aggregates. Additionally, anti-inflammatory and immunomodulatory capabilities are being integrated into immunoisolation devices to generate bioactive barriers that locally modulate host responses to encapsulated cells. Continued exploration of emerging paradigms governed by the inherent challenges associated with immunoisolation will be critical to actualizing the clinical potential of cell-based therapeutics.
John T. Wilsona Elliot L. ChaikofaEmail:echaiko@emory.edu
[a]Departments of Surgery and Biomedical Engineering, Emory University School of Medicine and the Georgia Institute of Technology, Atlanta, GA 30332, USA