Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.

/pdf/stem-cells-cancer-and-cancer-stem-cells-3s9b9ssybc.pdf

Stem cells, cancer, and cancer stem cells

We report here that cells co-purifying with mesenchymal stem cells--termed here multipotent adult progenitor cells or MAPCs--differentiate, at the single cell level, not only into mesenchymal cells, but also cells with visceral mesoderm, neuroectoderm and endoderm characteristics in vitro. When injected into an early blastocyst, single MAPCs contribute to most, if not all, somatic cell types. On transplantation into a non-irradiated host, MAPCs engraft and differentiate to the haematopoietic lineage, in addition to the epithelium of liver, lung and gut. Engraftment in the haematopoietic system as well as the gastrointestinal tract is increased when MAPCs are transplanted in a minimally irradiated host. As MAPCs proliferate extensively without obvious senescence or loss of differentiation potential, they may be an ideal cell source for therapy of inherited or degenerative diseases.

/pdf/pluripotency-of-mesenchymal-stem-cells-derived-from-adult-200s4qlizf.pdf

Pluripotency of mesenchymal stem cells derived from adult marrow

Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration

Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/20000/20530/JCI0320530.pdf

Epithelial-mesenchymal transition and its implications for fibrosis.

The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair.

Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts

Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell

It has recently been shown that specific lineage-depleted murine hematopoietic stem cells that home to the bone marrow 2 days after transplantation of ablated primary recipients are capable of long-term engraftment and repopulation of secondary recipients. We were interested in determining whether the rate at which the ablating radiation dose was delivered to the mice affected the homing of lineage-depleted stem cells to the bone marrow and/or sites of tissue damage. Fractionated, lineage-depleted donor marrow cells were isolated and labeled with the membrane dye PKH26. Recipient mice were lethally irradiated with 11 Gy ionizing radiation using varying dose rates and were immediately injected with PKH26-labeled progenitor stem cells. With the exception of the lowest dose-rate group, all irradiated mice had an approximately fivefold (P = 0.014 to 0.025) reduction in stem cell homing to the bone marrow compared to unirradiated control animals. A fivefold reduction of stem cell homing to the spleen compared to unirradiated animals was also observed, though this was not statistically significant for any dose-rate group (P = 0.072 to 0.233). This difference in homing could not be explained by increased stem cell apoptosis/necrosis or non-marrow tissue homing to the intestine, lung or liver. We show that the dose rate at which a lethal dose of total-body radiation is delivered does not augment hematopoietic progenitor stem cell homing to the bone marrow, spleen or sites of early radiation-mediated tissue damage at either 2 or 5 days postirradiation/transplantation. The observation that greater homing was seen in unirradiated control mice calls into question the concept that adequate bone marrow stem cell homing requires radiation-induced "space" to be made in the marrow, certainly for the enriched early progenitor hematopoietic stem cells used for this set of experiments. Further experiments will be needed to determine whether these homed cells are as capable of giving rise to long-term engraftment/repopulation of the marrow of secondary recipients as they are in irradiated recipients.

Hematopoietic Progenitor Stem Cell Homing in Mice Lethally Irradiated with Ionizing Radiation at Differing Dose Rates

Using an in vivo selection technique, we can isolate individual cells that can repopulate the hematopoietic system of a lethally irradiated murine recipient. These cells rapidly acquire a CD34 phenotype in the animal. Progenitors in our long-term chimeras are of donor type. We also have evidence that transplantation of limiting numbers (as low as a single cell) that have this long-term repopulating ability (LTRA) can self-renew. This is demonstrated by serial transplantation of marrow from engrafted recipients 11 months post transplant into new hosts for four additional months.

Sara Neutzel

Papers

Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell

Hematopoietic Progenitor Stem Cell Homing in Mice Lethally Irradiated with Ionizing Radiation at Differing Dose Rates

Phenotype and function of hematopoietic stem cells.