• Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428(6983):668-673. PubMed: 15034594. Categories: RepleniSENS

    Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.

    Nature 2004;428(6983):668-673.

    Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.

    Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC.

    Abstract

    Abstract:

    Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.

  • Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J, Taneera J, Fleischmann BK, Jacobsen SE. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004;10(5):494-501. PubMed: 15107841. Categories: RepleniSENS

    Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.

    Nat Med 2004;10(5):494-501.

    Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.

    Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J, Taneera J, Fleischmann BK, Jacobsen SE.

    Abstract

    Abstract:

    Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow-derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow-derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion.

  • Ben-Hur T, Idelson M, Khaner H, Pera M, Reinhartz E, Itzik A, Reubinoff BE. Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 2004;22(7):1246-1255. PubMed: 15579643. Categories: RepleniSENS

    Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats.

    Stem Cells 2004;22(7):1246-1255.

    Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats.

    Ben-Hur T, Idelson M, Khaner H, Pera M, Reinhartz E, Itzik A, Reubinoff BE.

    Abstract

    Abstract:

    Human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for transplantation. In Parkinson's disease, hESC-derived dopaminergic (DA) neurons may replace the degenerated neurons in the brain. Here, we generated highly enriched cultures of neural progenitors from hESCs and grafted the progenitors into the striatum of Parkinsonian rats. The grafts survived for at least 12 weeks, the transplanted cells stopped proliferating, and teratomas were not observed. The grafted cells differentiated in vivo into DA neurons, though at a low prevalence similar to that observed following spontaneous differentiation in vitro. Transplanted rats exhibited a significant partial correction of D-amphetamine and apomorphine-induced rotational behavior, along with a significant improvement in stepping and placing non-pharmacological behavioral tests. While transplantation of uncommitted hESC-derived neural progenitors induced partial behavioral recovery, our data indicate that the host-lesioned striatum could not direct the transplanted neural progenitors to acquire a dopaminergic fate. Hence, induction of their differentiation toward a midbrain fate prior to transplantation is probably required for complete correction of behavioral deficit. Our observations encourage further developments for the potential use of hESCs in the treatment of Parkinson's disease.

  • Nisbet MC. Public opinion about stem cell research and human cloning. Public Opinion Quarterly 2004;68(1):131-154. Categories: Beyond the Bench, RepleniSENS

    Public opinion about stem cell research and human cloning.

    Public Opinion Quarterly 2004;68(1):131-154.

    Public opinion about stem cell research and human cloning.

    Nisbet MC.

    Abstract

    Abstract:

    No abstract available.

  • Hodgson DM, Behfar A, Zingman LV, Kane GC, Perez-Terzic C, Alekseev AE, Puceat M, Terzic A. Stable benefit of embryonic stem cell therapy in myocardial infarction. Am J Physiol Heart Circ Physiol 2004;287(2):H471-H479. PubMed: 15277190. Categories: RepleniSENS

    Stable benefit of embryonic stem cell therapy in myocardial infarction.

    Am J Physiol Heart Circ Physiol 2004;287(2):H471-H479.

    Stable benefit of embryonic stem cell therapy in myocardial infarction.

    Hodgson DM, Behfar A, Zingman LV, Kane GC, Perez-Terzic C, Alekseev AE, Puceat M, Terzic A.

    Abstract

    Abstract:

    Conventional therapies for myocardial infarction attenuate disease progression without contributing significantly to repair. Because of the capacity for de novo cardiogenesis, embryonic stem cells are considered a potential source for myocardial regeneration, yet limited information is available on their ultimate therapeutic value. We treated infarcted rat hearts with CGR8 embryonic stem cells preexamined for cardiogenicity, serially probed left ventricular function, and determined final pathological outcome. Stem cell delivery generated new cardiomyocytes of embryonic stem cell origin that integrated with host myocardium within infarct regions. This resulted in a functional benefit within 3 wk that remained sustained over 12 wk of continuous follow-up and included a vigorous inotropic response to beta-adrenergic challenge. Integration of stem cell-derived cardiomyocytes was associated with normalized ventricular architecture, little scar, and a decrease in signs of myocardial necrosis. In contrast, sham-treated infarcted hearts exhibited ventricular cavity dilation and aneurysm formation, poor ventricular function, and a lack of response to beta-adrenergic stimulation. No evidence of graft rejection, ectopy, sudden cardiac death, or tumor formation was observed after therapy. These findings indicate that embryonic stem cells, through differentiation within the host myocardium, can contribute to a stable beneficial outcome on contractile function and ventricular remodeling in the infarcted heart.

  • Atala A. Tissue engineering and regenerative medicine: concepts for clinical application. Rejuvenation Res 2004;7(1):15-31. PubMed: 15256042. Categories: RepleniSENS

    Tissue engineering and regenerative medicine: concepts for clinical application.

    Rejuvenation Res 2004;7(1):15-31.

    Tissue engineering and regenerative medicine: concepts for clinical application.

    Atala A.

    Abstract

    Abstract:

    Patients suffering from diseased and injured organs may be treated with transplanted organs. However, there is a severe shortage of donor organs that is worsening yearly given the aging population. Scientists in the field of regenerative medicine and tissue engineering apply the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Therapeutic cloning, where the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells, offers a potentially limitless source of cells for tissue engineering applications. The stem cell field is also advancing rapidly, opening new options for therapy. This paper reviews recent advances that have occurred in regenerative medicine and describes applications of these new technologies that may offer novel therapies for patients with end-stage organ failure.

  • Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 2003;21(10):1200-1207. PubMed: 14502203. Categories: RepleniSENS

    Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice.

    Nat Biotechnol 2003;21(10):1200-1207.

    Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice.

    Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L.

    Abstract

    Abstract:

    Existing protocols for the neural differentiation of mouse embryonic stem (ES) cells require extended in vitro culture, yield variable differentiation results or are limited to the generation of selected neural subtypes. Here we provide a set of coculture conditions that allows rapid and efficient derivation of most central nervous system phenotypes. The fate of both fertilization- and nuclear transfer-derived ES (ntES) cells was directed selectively into neural stem cells, astrocytes, oligodendrocytes or neurons. Specific differentiation into gamma-aminobutyric acid (GABA), dopamine, serotonin or motor neurons was achieved by defining conditions to induce forebrain, midbrain, hindbrain and spinal cord identity. Neuronal function of ES cell-derived dopaminergic neurons was shown in vitro by electron microscopy, measurement of neurotransmitter release and intracellular recording. Furthermore, transplantation of ES and ntES cell-derived dopaminergic neurons corrected the phenotype of a mouse model of Parkinson disease, demonstrating an in vivo application of therapeutic cloning in neural disease.

  • Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422(6934):897-901. PubMed: 12665832. Categories: RepleniSENS

    Cell fusion is the principal source of bone-marrow-derived hepatocytes.

    Nature 2003;422(6934):897-901.

    Cell fusion is the principal source of bone-marrow-derived hepatocytes.

    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M.

    Abstract

    Abstract:

    Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.

  • Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM,Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003;425(6961):968-973. PubMed: 14555960. Categories: RepleniSENS

    Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

    Nature 2003;425(6961):968-973.

    Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM,Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A.

    Abstract

    Abstract:

    Recent studies have suggested that bone marrow cells possess a broad differentiation potential, being able to form new liver cells, cardiomyocytes and neurons. Several groups have attributed this apparent plasticity to 'transdifferentiation'. Others, however, have suggested that cell fusion could explain these results. Using a simple method based on Cre/lox recombination to detect cell fusion events, we demonstrate that bone-marrow-derived cells (BMDCs) fuse spontaneously with neural progenitors in vitro. Furthermore, bone marrow transplantation demonstrates that BMDCs fuse in vivo with hepatocytes in liver, Purkinje neurons in the brain and cardiac muscle in the heart, resulting in the formation of multinucleated cells. No evidence of transdifferentiation without fusion was observed in these tissues. These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types.

  • Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422(6934):901-904. PubMed: 12665833. Categories: RepleniSENS

    Transplanted bone marrow regenerates liver by cell fusion.

    Nature 2003;422(6934):901-904.

    Transplanted bone marrow regenerates liver by cell fusion.

    Vassilopoulos G, Wang PR, Russell DW.

    Abstract

    Abstract:

    Results from several experimental systems suggest that cells from one tissue type can form other tissue types after transplantation. This could be due to the presence of multipotential or several types of adult stem cells in donor tissues, or alternatively, to fusion of donor and recipient cells. In a model of tyrosinaemia type I, mice with mutations in the fumarylacetoacetate hydrolase gene (Fah-/-) regain normal liver function after transplantation of Fah+/+ bone marrow cells, and form regenerating liver nodules with normal histology that express Fah. Here we show that these hepatic nodules contain more mutant than wild-type Fah alleles, and that their hepatocytes express both donor and host genes, consistent with polyploid genome formation by fusion of host and donor cells. Using bone marrow cells marked with integrated foamy virus vectors that express green fluorescent protein, we identify common proviral junctions in hepatic nodules and haematopoietic cells. We also show that the haematopoietic donor genome adopts a more hepatocyte-specific expression profile after cell fusion, as the wild-type Fah gene was activated and the pan-haematopoietic CD45 marker was no longer expressed.

  • Mangi AA, Noiseux N, Kong D, Mangi AA, Noiseux N, Kong D. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003;9(9):1195-1201. PubMed: 12910262. Categories: RepleniSENS

    Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts.

    Nat Med 2003;9(9):1195-1201.

    Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts.

    Mangi AA, Noiseux N, Kong D, Mangi AA, Noiseux N, Kong D.

    Abstract

    Abstract:

    Transplantation of adult bone marrow-derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80-90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.

  • Hoffman DI, Zellman GL, Fair CC, Mayer JF, Zeitz JG, Gibbons WE, Turner TG Jr; Society for Assisted Reproduction Technology (SART) and RAND. Cryopreserved embryos in the United States and their availability for research. Fertil Steril 2003;79(5):1063-1069. PubMed: 12738496. Categories: RepleniSENS

    Cryopreserved embryos in the United States and their availability for research.

    Fertil Steril 2003;79(5):1063-1069.

    Cryopreserved embryos in the United States and their availability for research.

    Hoffman DI, Zellman GL, Fair CC, Mayer JF, Zeitz JG, Gibbons WE, Turner TG Jr; Society for Assisted Reproduction Technology (SART) and RAND.

    Abstract

    Abstract:

    OBJECTIVE: To determine the number of embryos stored at assisted reproductive technology (ART) clinics in the United States and their current disposition. DESIGN: A targeted survey instrument sent by the SART-RAND team to all medical practices providing in vitro fertilization services in the United States. RESULTS: The SART-RAND team surveyed all 430 ART practices in the United States. Of these practices, 340 returned surveys for analysis. The data from these surveys were merged with data taken from the 1999 SART dataset, which contains information about practice size and success rates. Responding clinics reported a total of 396,526 embryos in storage as of April 11, 2002. The vast majority of the embryos (88.2%) were targeted for patient use. Small numbers of embryos were available for research, donation, destruction, quality assurance, or other uses. CONCLUSIONS: Nearly 400,000 embryos are stored in the United States, the majority of which (88.2%) are targeted for patient use. Few are available for research (2.8%), limiting possible conversion into embryonic stem cell lines.

  • Min JY, Yang Y, Sullivan MF, Ke Q, Converso KL, Chen Y, Morgan JP, Xiao YF. Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. J Thorac Cardiovasc Surg 2003;125(2):361-369. PubMed: 12579106. Categories: RepleniSENS

    Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells.

    J Thorac Cardiovasc Surg 2003;125(2):361-369.

    Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells.

    Min JY, Yang Y, Sullivan MF, Ke Q, Converso KL, Chen Y, Morgan JP, Xiao YF.

    Abstract

    Abstract:

    OBJECTIVE: This study was designed to investigate the feasibility of and potential functional improvement with embryonic stem cell transplantation in rats 32 weeks after myocardial infarction. METHODS: Before cell transplantation, cultured embryonic stem cells were transfected with the complementary DNA of green fluorescent protein to identify engrafted cells in myocardium. Myocardial infarction was induced by ligation of the left coronary artery. Either 3 x 10(5) mouse embryonic stem cells or an equivalent volume of cell-free medium was injected into injured myocardium within 20 minutes after induction of myocardial infarction. RESULTS: Embryonic stem cell transplantation significantly increased the survival rate in rats undergoing myocardial infarction during the experimental period of 32 weeks. Hemodynamic and echocardiographic data showed that embryonic stem cell transplantation significantly improved ventricular function relative to the myocardial infarction plus medium control group. Tissue positive for green fluorescent protein was found in the injured myocardium with cell transplantation. The proportion of myocardium positively immunostained by antibodies against alpha-myosin heavy chain and cardiac troponin I was greater in the infarcted area with embryonic stem cell transplantation than in the injured myocardium with medium injection. Single green fluorescent protein-positive cells with a rod shape and clear striations were observed in cardiomyocytes isolated from infarcted hearts with embryonic stem cell transplantation. In addition, the number of blood vessels in injured myocardium was greater in the cell-transplanted myocardial infarction group than in the medium-injected myocardial infarction group. CONCLUSIONS: Engrafted embryonic stem cells differentiated into cardiomyocytes in injured myocardium, caused an angiogenetic effect, and subsequently improved cardiac function during the 32-week observation period.

  • Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 2002;99(25):16105-16110. PubMed: 12441403. Categories: RepleniSENS

    Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.

    Proc Natl Acad Sci USA 2002;99(25):16105-16110.

    Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.

    Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK.

    Abstract

    Abstract:

    The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic beta cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.

  • Lanza RP, Chung HY, Yoo JJ, Wettstein PJ, Blackwell C, Borson N, Hofmeister E, Schuch G, Soker S, Moraes CT, West MD, Atala A. Generation of histocompatible tissues using nuclear transplantation. Nat Biotechnol 2002;20(7):689-696. PubMed: 12089553. Categories: RepleniSENS

    Generation of histocompatible tissues using nuclear transplantation.

    Nat Biotechnol 2002;20(7):689-696.

    Generation of histocompatible tissues using nuclear transplantation.

    Lanza RP, Chung HY, Yoo JJ, Wettstein PJ, Blackwell C, Borson N, Hofmeister E, Schuch G, Soker S, Moraes CT, West MD, Atala A.

    Abstract

    Abstract:

    Nuclear transplantation (therapeutic cloning) could theoretically provide a limitless source of cells for regenerative therapy. Although the cloned cells would carry the nuclear genome of the patient, the presence of mitochondria inherited from the recipient oocyte raises questions about the histocompatibility of the resulting cells. In this study, we created bioengineered tissues from cardiac, skeletal muscle, and renal cells cloned from adult bovine fibroblasts. Long-term viability was demonstrated after transplantation of the grafts into the nuclear donor animals. Reverse transcription-PCR (RT-PCR) and western blot analysis confirmed that the cloned tissues expressed tissue-specific mRNA and proteins while expressing a different mitochondrial DNA (mtDNA) haplotype. In addition to creating skeletal muscle and cardiac "patches", nuclear transplantation was used to generate functioning renal units that produced urinelike fluid and demonstrated unidirectional secretion and concentration of urea nitrogen and creatinine. Examination of the explanted renal devices revealed formation of organized glomeruli- and tubule-like structures. Delayed-type hypersensitivity (DTH) testing in vivo and Elispot analysis in vitro suggested that there was no rejection response to the cloned renal cells. The ability to generate histocompatible cells using cloning techniques addresses one of the major challenges in transplantation medicine.

  • Rideout WM, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 2002;109(1):17-27. PubMed: 11955443. Categories: RepleniSENS

    Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy.

    Cell 2002;109(1):17-27.

    Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy.

    Rideout WM, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R.

    Abstract

    Abstract:

    Immune-deficient Rag2(-/-) mice were used as nuclear donors for transfer into enucleated oocytes, and the resulting blastocysts were cultured to isolate an isogenic embryonic stem cell line. One of the mutated alleles in the Rag2(-/-) ES cells was repaired by homologous recombination, thereby restoring normal Rag2 gene structure. Mutant mice were treated with the repaired ES cells in two ways. (1) Immune-competent mice were generated from the repaired ES cells by tetraploid embryo complementation and were used as bone marrow donors for transplantation. (2) Hematopoietic precursors were derived by in vitro differentiation from the repaired ES cells and engrafted into mutant mice. Mature myeloid and lymphoid cells as well as immunoglobulins became detectable 3-4 weeks after transplantation. Our results establish a paradigm for the treatment of a genetic disorder by combining therapeutic cloning with gene therapy.

  • Park KI, Teng YD, Snyder EY. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol 2002;20(11):1111-1117. PubMed: 12379868. Categories: RepleniSENS

    The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue.

    Nat Biotechnol 2002;20(11):1111-1117.

    The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue.

    Park KI, Teng YD, Snyder EY.

    Abstract

    Abstract:

    Hypoxic-ischemic injury is a prototype for insults characterized by extensive tissue loss. Seeding neural stem cells (NSCs) onto a polymer scaffold that was subsequently implanted into the infarction cavities of mouse brains injured by hypoxia-ischemia allowed us to observe the multiple reciprocal interactions that spontaneously ensue between NSCs and the extensively damaged brain: parenchymal loss was dramatically reduced, an intricate meshwork of many highly arborized neurites of both host- and donor-derived neurons emerged, and some anatomical connections appeared to be reconstituted. The NSC-scaffold complex altered the trajectory and complexity of host cortical neurites. Reciprocally, donor-derived neurons were seemingly capable of directed, target-appropriate neurite outgrowth (extending axons to the opposite hemisphere) without specific external instruction, induction, or genetic manipulation of host brain or donor cells. These "biobridges" appeared to unveil or augment a constitutive reparative response by facilitating a series of reciprocal interactions between NSC and host, including promoting neuronal differentiation, enhancing the elaboration of neural processes, fostering the re-formation of cortical tissue, and promoting connectivity. Inflammation and scarring were also reduced, facilitating reconstitution.

  • Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297(5590):2256-2259. PubMed: 12215650. Categories: RepleniSENS

    Little evidence for developmental plasticity of adult hematopoietic stem cells.

    Science 2002;297(5590):2256-2259.

    Little evidence for developmental plasticity of adult hematopoietic stem cells.

    Wagers AJ, Sherwood RI, Christensen JL, Weissman IL.

    Abstract

    Abstract:

    To rigorously test the in vivo cell fate specificity of bone marrow (BM) hematopoietic stem cells (HSCs), we generated chimeric animals by transplantation of a single green fluorescent protein (GFP)-marked HSC into lethally irradiated nontransgenic recipients. Single HSCs robustly reconstituted peripheral blood leukocytes in these animals, but did not contribute appreciably to nonhematopoietic tissues, including brain, kidney, gut, liver, and muscle. Similarly, in GFP+:GFP- parabiotic mice, we found substantial chimerism of hematopoietic but not nonhematopoietic cells. These data indicate that "transdifferentiation" of circulating HSCs and/or their progeny is an extremely rare event, if it occurs at all.

  • Cibelli JB, Kiessling A, Cunniff K, Richards C, Lanza RP, West MD. Somatic cell nuclear transfer in humans: pronuclear and early embryonic development. e-biomed: J Regenerative Med 2001;2:25–31. Categories: RepleniSENS

    Somatic cell nuclear transfer in humans: pronuclear and early embryonic development.

    e-biomed: J Regenerative Med 2001;2:25–31.

    Somatic cell nuclear transfer in humans: pronuclear and early embryonic development.

    Cibelli JB, Kiessling A, Cunniff K, Richards C, Lanza RP, West MD.

    Abstract

    Abstract:

    No abstract available.

  • Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci USA 2000;97(11):6126-6131. PubMed: 10823956. Categories: RepleniSENS

    Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation.

    Proc Natl Acad Sci USA 2000;97(11):6126-6131.

    Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation.

    Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW.

    Abstract

    Abstract:

    Demyelination contributes to the loss of function consequent to central nervous system (CNS) injury. Enhanced remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. An unlimited source of cells suitable for such transplantation therapy can be derived from embryonic stem (ES) cells, which are both pluripotent and genetically flexible. In this paper we show that oligodendrocyte cultures can be reliably produced from retinoic acid-induced ES cells and that these oligodendrocytes can myelinate axons in vitro. Methods were further developed for generating highly enriched cultures of oligodendrocytes through an additional culturing step, producing an intermediate "oligosphere" stage. To test whether ES cells can survive, migrate, and differentiate into mature myelin-producing cells in areas of demyelination in the adult CNS, ES cells were transplanted into the dorsal columns of adult rat spinal cord 3 days after chemical demyelination. In the demyelination site, large numbers of ES cells survived and differentiated primarily into mature oligodendrocytes that were capable of myelinating axons. Furthermore, when oligosphere cells were transplanted into the spinal cords of myelin-deficient shiverer (shi/shi) mutant mice, the ES cell-derived oligodendrocytes migrated into the host tissue, produced myelin and myelinated host axons. These studies demonstrate the ability of ES cell-derived oligodendrocytes to myelinate axons in culture and to replace lost myelin in the injured adult CNS. Transplantation of ES cells may be a practical approach to treatment of primary and secondary demyelinating diseases in the adult CNS.

  • McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 1999;5(12):1410-1412. PubMed: 10581084. Categories: RepleniSENS

    Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.

    Nat Med 1999;5(12):1410-1412.

    Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.

    McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW.

    Abstract

    Abstract:

    Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.

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