Showing papers by "Diane S. Krause published in 2002"

Plasticity of marrow-derived stem cells.

Abstract: Many exciting discoveries reported over the past 3 years have caused us to expand the paradigm for understanding somatic stem cell plasticity. Within adult organs, there are not only specific stem cells that are capable of producing functional cells of one organ system, but also cells with the flexibility to differentiate into multiple other cell types. In the bone marrow, for example, in addition to hematopoietic stem cells and supportive stromal cells, there are cells with the potential to differentiate into mature cells of the heart, liver, kidney, lungs, GI tract, skin, bone, muscle, cartilage, fat, endothelium and brain. A subpopulation of cells in the brain can differentiate into all of the major cell types in the brain and also into hematopoietic and skeletal muscle cells. In this brief overview, several of these recent findings are summarized.

Rapid Communication Marrow-Derived Cells as Vehicles for Delivery of Gene Therapy to Pulmonary Epithelium

Abstract: Gene therapy application to pulmonary airways and alveolar integrate into target cell DNA and have been effectively spaces holds tremendous promise for the treatment of lung used for efficient transduction of murine, canine, nonhuman diseases. However, safe and effective long-term gene expres- primate, and human hematopoietic stem and progenitor sion using viral and nonviral vectors has not yet been achieved. cells (5–11). Adenoviral vectors, with a natural affinity for airway epithelia, We have shown that a single bone marrow–derived stem have been partially effective, but are inflammatory and induce cell (BMSC) can reconstitute not only the hematopoietic only transient gene expression. We investigate the novel ap- system, but also can engraft as mature epithelial cells in proach of using retrovirally transduced multipotent bone mar- the liver, lung, GI tract, and skin (12). These data suggest row–derived stem cells (BMSC) to deliver gene therapy to lung that, if these BMSCs can be stably transduced and maintain epithelium. We have shown previously that up to 20% of lung their plasticity, then they could be an ideal cell population epithelial cells can be derived from marrow following BMSC for the delivery of therapeutic genes to nonhematopoietic transplantation. Here, irradiated female mice were transplanted tissues. In the experiments reported herein, we tested this

Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium

Abstract: Gene therapy application to pulmonary airways and alveolar spaces holds tremendous promise for the treatment of lung diseases. However, safe and effective long-term gene expression using viral and nonviral vectors has not yet been achieved. Adenoviral vectors, with a natural affinity for airway epithelia, have been partially effective, but are inflammatory and induce only transient gene expression. We investigate the novel approach of using retrovirally transduced multipotent bone marrow-derived stem cells (BMSC) to deliver gene therapy to lung epithelium. We have shown previously that up to 20% of lung epithelial cells can be derived from marrow following BMSC transplantation. Here, irradiated female mice were transplanted with male marrow that had been transduced with retrovirus encoding eGFP. Transgene expressing lung epithelial cells were present in all recipients analyzed at 2, 5, or 11 mo after transplant (n = 10), demonstrating that highly plastic BMSC can be stably transduced in vitro and retain their ability to differentiate into lung epithelium while maintaining long-term transgene expression.

Regulation of hematopoietic stem cell fate

Abstract: By de®nition, a hematopoietic stem cell (HSC) is capable both of unlimited self-renewal and di€erentiation into all mature peripheral blood types. Hematopoietic di€erentiation can be viewed as a tree with the HSC represented by the trunk (or `stem') and each of the committed progenitors and their more committed progeny represented by the branches. The mechanisms that control whether a HSC self-renews or di€erentiates remain a mystery. However, many of the important players in this regulation have been identi®ed. The transcriptional regulation of hematopoiesis has been studied in several di€erent organisms and many transcription factors have been identi®ed that specify whether hematopoietic stem cells di€erentiate down the myeloid, lymphoid, or erythromegakaryocytic lineages. One of the themes that has grown more apparent over years of study is that the critical pathways that control HSC and their progeny are shared by other stem and progenitor cell types throughout the body and throughout phylogeny. The transcriptional regulation of erythropoiesis, lymphopoiesis and myelopoiesis is already covered in detail in other manuscripts in this issue of Oncogene. This review focuses on components of the cellular microenvironment that regulate HSC di€erentiation, and on the gene expression patterns that play a role in maintaining a stem cell in its undi€erentiated state. These ®ndings are placed into context with other tissue systems and other organisms.

Toward a new paradigm of cell plasticity.

Abstract: The standard paradigm of embryologic development and adult tissue reconstitution posits unidirectional, hierarchical lineages. The presumed mechanisms underlying these differentiative pathways are gene restrictions, such as methylation and heterochromatin formation, which are commonly described as irreversible. However, recent discoveries regarding multi-organ stem cells demonstrate that 'true plasticity' exists, with cells of one organ turning into cells of other organs, including differentiative transformations that cross barriers between tissues derived from different primitive germ layers. These findings, along with earlier experiments into heterokaryon formation and longstanding recognition of reactive and neoplastic lesions in humans and animals, suggest that lineage pathways are not, in fact, unidirectional. Moreover, physiologic mechanisms of reversal of gene restrictions have been recognized. Therefore, in response to these observations, we suggest a new paradigm of cell plasticity, elucidating three guiding principles of 'genomic completeness', 'uncertainty of cell characterization', and 'stochastic nature of cell origins and fates'. These principles imply a change in the way data can be interpreted and could alter subsequent hypothesis formation. This new paradigm will hopefully lead us forward to a more flexible and creative exploration of the potential of adult vertebrate cells.

Multi-organ engraftment with a single bone marrow-derived stem cell

Abstract: Purification of rare Hematopoietic Stem Cells (HSC) to homogeneity is required to study their self-renewal, differentiation, phenotype, survival, and homing. Long-term repopulation (LTR) of irradiated hosts and serial transplantation to secondary hosts are the gold standard for demonstrating self renewal and differentiation, the defining properties of HSC's. We show that selection of rare cells that home rapidly to the bone marrow enriches for individual cells that can LTR primary and secondary recipients. During the procedure, CD34 and SCA-1 expression increases uniquely on cells that home to marrow. These adult bone marrow cells have nearly embryonic differentiation potential as they can also differentiate into epithelial cells of the liver, lung, GI tract, and skin. This finding is of great scientific importance and can be applied to clinical treatment of genetic disease or tissue repair.