Showing papers by "Markus Grompe published in 2006"

Bone marrow-derived cells fuse with normal and transformed intestinal stem cells

Abstract: Transplanted adult bone marrow-derived cells (BMDCs) have been shown to adopt the phenotype and function of several nonhematopoietic cell lineages and promote tumorigenesis. Beyond its cancer enhancing potential, cell fusion has recently emerged as an explanation of how BMDCs regenerate diseased heptocytes, contribute to Purkinje neurons and skeletal and cardiac muscle cells, and participate in skin and heart regeneration. Although bone marrow-derived epithelial cells also have been observed in the intestine, fusion as a mechanism has not been investigated. Here, we show that transplanted BMDCs fuse with both normal and neoplastic intestinal epithelium. Long-term repopulation by donor-derived cells was detected in all principal intestinal epithelial lineages including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, suggesting that the fusion partners of the BMDCs are long-lived intestinal progenitors or stem cells. Fusion of BMDCs with neoplastic epithelium did not result in tumor initiation. Our findings suggest an unexpected role for BMDCs in both regeneration and tumorigenesis of the intestine.

Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice

Abstract: Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSA-overexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients.

Myeloid lineage progenitors give rise to vascular endothelium

Abstract: Despite an important role in vascular development and repair, the origin of endothelial progenitors remains unknown. Accumulating evidence indicates that cells derived from the hematopoietic system participate in angiogenesis. However, the identity and functional role of these cells remain controversial. Here we show that vascular endothelial cells can differentiate from common myeloid progenitors and granulocyte/macrophage progenitors. Endothelial cells derived from transplanted bone marrow-derived myeloid lineage progenitors expressed CD31, von Willebrand factor, and Tie2 but did not express the hematopoietic markers CD45 and F4/80 or the pericyte markers desmin and smooth muscle actin. Lineage tracing analysis in combination with a Tie2-driven Cre/lox reporter system revealed that, in contrast to bone marrow-derived hepatocytes, bone marrow-derived endothelial cells are not the products of cell fusion. The establishment of both hematopoietic and endothelial cell chimerism after parabiosis demonstrates that circulating cells can give rise to vascular endothelium in the absence of acute radiation injury. Our findings indicate that endothelial cells are an intrinsic component of myeloid lineage differentiation and underscore the close functional relationship between the hematopoietic and vascular systems.

Principles of therapeutic liver repopulation.

Abstract: Liver repopulation by transplanted hepatocytes is a promising approach for many inborn errors of metabolism. In this review, examples of liver repopulation in animals and the implications of these models for clinical cell transplantation will be discussed.

Seeking consensus: a clarification and defense of altered nuclear transfer.

Abstract: Since 1998, when human embryonic stem cells were first isolated, our nation has been locked in a conflict over federal funding of this new field of scientific research. Both sides in the debate are defending important human goods, and both of these goods--opening avenues for advance in medicine and protecting nascent human life are important to all of us. A purely political solution will leave our country bitterly divided, eroding the social support and sense of noble purpose that is essential for the public funding of biomedical science. While there are currently no federal restrictions on the use of private funds for this research, there is a consensus in the scientific community that without federal support for newly created embryonic stem cell lines, progress in this emerging field of scientific inquiry will be seriously constrained. In May 2005, acknowledging our national impasse over embryonic stem cell research, the President's Council on Bioethics published a white paper that outlines a series of proposals for obtaining pluripotent stem cells (the functional equivalent of embryonic stem cells) without the creation or destruction of human embryos. (1) One of these proposals, "altered nuclear transfer" (ANT) has stirred considerable public interest and affirmation, including several legislative proposals that would provide funding for its further exploration. There is substantial support among leading scientists, moral philosophers, and religious leaders for the view that ANT may offer a scientifically feasible and morally sound way forward on ES cell research. (2) At the same time, there has been some confusion about ANT, leading to its mischaracterization in certain reports and published commentaries. In a recent cover story on stem cell research in Time magazine, ANT was described as a project that "would ensure that the embryo lives only long enough to produce stem cells and then dies." (3) But the whole idea of ANT is to produce pluripotent stem cells without creating an embryo. Time's description has ANT violating the very moral principle it is intended to uphold. Acknowledging the complexity of the scientific and ethical issues at the foundation of this proposal, and in the spirit of constructive dialogue, we seek in this essay first to offer a clear and accurate account of ANT, and then to respond to some of the more significant questions and concerns about it. Altered Nuclear Transfer: Non-Embryonic Sources of Pluripotent Cells The President's Council report draws a critical distinction between pluripotency, the capacity of a cell to give rise to many if not all the different cell types of the human body, and totipotency, the capacity of a zygote or other cell to develop as a complete, integrated, living being. A naturally conceived zygote--the single-celled embryo brought into being by fertilization--is totipotent; embryonic stem cells are merely pluripotent. ANT is a general concept that might take a variety of specific forms. The basic idea is to employ somatic cell nuclear transfer (SCNT), the technique often known simply as "cloning," but to alter it in such a way that pluripotent stem cells are produced without the creation and destruction of human embryos. In standard SCNT, the nucleus of a differentiated body cell is transferred into an egg cell that has had its own nucleus removed. (4) The egg cytoplasm then reprograms the transferred nucleus and, if all goes as planned, the newly constituted cell proceeds to divide and develop like a naturally conceived embryo. This is how Dolly the sheep was produced. In ANT, the adult body cell nucleus or the egg cytoplasm (or both) are altered before the nucleus is transferred into the enucleated egg so that the newly constituted cell will, from the outset, lack the integrated unity and developmental potential of an embryo, yet will nevertheless possess the capacity for a certain limited subset of growth sufficient to produce pluripotent stem cells. …