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Less Food, Better Haematopoietic Function?

Fasting for an extended period of time is shown to protect and enhance the function of the hematopoietic system through signalling mechanisms involving IGF-1 and PKA

Human Stem Cell Gene Therapy – Safe and Effective

Two recent studies in Science reporting the outcome of lentivirally-mediated gene correction in hematopoietic stem cells (HSCs) to treat human patients have potentially ushered in a new era of safe and effective gene therapy.   Herein, we report on these exciting new clinical findings, both from the laboratory of Luigi Naldini at the San Raffaele Scientific Institute, Milan, Italy, on the treatment of metachromatic leukodystrophy (MLD), caused by mutations in the arylsulfatase A (ARSA) gene, and Wiskott-Aldrich syndrome (WAS), caused by mutations in the gene encoding WASP.

Antibody Mediated Transdifferentiation

"Autocrine signaling based selection of combinatorial antibodies that transdifferentiate human stem cells"

The group of Richard A. Lerner at The Scripps Research Institute, La Jolla, CA have previously described a means of expressing antibodies through lentiviral infection of cells and studying how the cells are affected in an autocrine manner (Zhang et al) through interactions with membrane bound co-expressed receptors. In a recent report in PNAS they now describe a co-expression system of an antibody library with the granulocyte colony-stimulating factor receptor (G-CSFR), and have isolated agonist antibodies which can transdifferentiate human CD34+ haematopoietic stem cells (HSCs) into neural progenitor cells (NPCs) (Xie et al).

Protecting Haematopoietic Stem Cells from Radiation

Original article from STEM CELLS

"Prostaglandin E2 Increases Hematopoietic Stem Cell Survival and Accelerates Hematopoietic Recovery After Radiation Injury"

Modulation of the bone marrow microenvironment to allow the expansion and engraftment of hematopoietic stem and progenitor cells (HSPCs) following transplantation has shown some success (Adams et al, Bormberg et al, Calvi et al and Mendez-Ferrer et al). Prostaglandin E2 (PGE2) has recently been shown to improve HSPC repopulating ability through the activation of EP2 and EP4 receptors (Goessling et al, Hoggatt et al and North et al) but little is known of the distinct mechanisms behind this action (Frisch et al). In a recent study published in Stem Cells, researchers from the laboratory of Laura M. Calvi at the University of Rochester School of Medicine, New York have shown that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate and decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity (Porter et al).

Exciting new treatment AID under trial for HIV

Prominent Australian stem cell scientist and current Director of the California Institute of Regenerative Medicine (CIRM) Professor Alan Trounson has announced that a potential cure for HIV is about to enter human clinical trials. The treatment takes advantage of the fact that a small proportion of humans are immune to HIV as they have a specific gene mutation which disables the CCR5 receptor that the HIV virus needs to invade cells of the immune system. The research about to be trialled utilises blood stem cells carrying this mutation to armour the body against HIV, which will be delivered to patients in the form of a bone marrow transplant. This approach follows in the wake of the ‘Berlin patient’ Timothy Brown, the only known person worldwide to have been cured of HIV following a life-saving bone marrow transplant from a donor carrying the HIV-resistant mutation to treat leukaemia.   Introducing immune cells which have a disabled HIV receptor effectively stops the virus reproducing, but does not cause any harmful effects to the patient. Prof. Trounson however stated that even if the trials are successful it may take another six to seven years before the treatment is widely available, but if the treatment works properly could cure patients of the infection and eliminate the need for lifelong antiviral drugs.   He also stated that this approach will require careful scrutiny as bone marrow transplants can pose significant risks and side effects, given that antiviral drug medication currently allows HIV patients 30 to 40 years of relatively good health. It may also need further modification to allow affordable access to patients where the disease is most prevalent, in sub-Saharan Africa.

Proof of principle for transfusion of in vitro generated red blood cells

From Blood
By Stuart P. Atkinson

The chronic lack of donated blood, with an annual requirement of nearly 90 million units worldwide presents a major problem which, with an increasing world population, will only get worse. Apart from typical blood donation, another possible source of blood cells is through in vitro manipulations of stem cell populations, such as circulating haematopoietic stem cells (HSCs) or, potentially, embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs); the latter being particularly attractive for patients with blood-related disease. The advantages of stem cell-derived blood are many; these could potentially provide an unlimited source of the various blood types, and reduce the risk of infectious disease from donated blood. However, to date, the transfusion potential of stem cell-derived blood products generated in vitro has yet to be assessed in man. Now in a study (Giarratana et al) from the group of Luc Douay at UPMC University Paris, France, published online in Blood, these issues have been addressed. They report that in vitro-derived reticulocytes (cultured red blood cells; cRBCs) have a similar functional capacity to native reticulocytes, can mature appropriately in mouse and, importantly, they report the successful transfusion and in vivo survival of cRBCs in a human patient.

Efficient Generation of Hematopoietic Precursors and Progenitors from Human Pluripotent Stem Cell Lines

From the July Edition of Stem Cells
By Stuart P. Atkinson

The study of embryonic development of the hematopoietic system has allowed us to uncover many of the key molecular mechanisms that act at the various different stages. Taking such information into consideration, Woods et al from the lab of Inder M. Verma at the Salk Institute for Biological Studies, La Jolla, California, USA have optimized an in vitro differentiation protocol for the generation of precursors of the hematopoietic lineage and primitive hematopoietic cells from human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs).

There Will be Blood: Isolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment

From Science
By Stuart P. Atkinson

A recent Stem Cells article (Woods et al) and associated review on the Stem Cells Portal described an optimized in vitro differentiation protocol for the generation of precursors of the hematopoietic lineage and primitive hematopoietic cells from human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs). The authors themselves note however that this protocol failed to derive long-term repopulating haematopoietic stem cells (HSCs). This suggests either that the protocol is incomplete, maybe lacking certain key signals at necessary time-points, and/or that the cell surface markers used were insufficient to purify those cells capable of long-term repopulation and engraftment. In a recent paper in Science, researchers from the laboratory of John E. Dick at the Toronto Medical Discovery Tower, Toronto, Canada have identified key cell surface markers which now allow the purification of HSCs with long-term engraftment and serial transplantation ability and importantly, single-cell engraftment; the definitive assessment of HSC potential (Notta et al, 2011).

Prostate cancer metastases directly compete with hematopoietic stem cells for occupancy of the stem cell niche

From the Journal of Clinical Investigation

Results from a recent study published in the Journal of Clinical Investigation by Shiozawa et al. from the University of Michigan and Harvard School of Dental Medicine provide new evidence for the mechanisms directing metastases of carcinomas into bone tissue, observed in 70% of patients with breast or prostate cancer and up to 30% of patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney carcinomas. Their work reveals that metastases target the skeleton by taking advantage of signals normally present in the hematopoietic stem cell (HSC) niche that are known to regulate HSC homing, quiescence and self renewal. Using a mouse model of metastasis, the authors demonstrate that metastasised human prostate cancer cells (PCa) directly compete with HSCs for residency within the HSC niche, preventing HSC engraftment by occupying the HSC niche and driving out HSCs into progenitor pools and the peripheral blood by driving HSC terminal differentiation. Further, they demonstrate the co-localisation of PCa cells and HSCs to the endosteal niche of the bone marrow, particularly to Anxa2-expressing osteoblasts (known to play a central role in HSC niche selection), indicating this to be the site of the HSC niche, the exact location and composition of which has been a controversial issue until now. Interestingly, decreasing the HSC niche size by ablating osteoblastic lineage cells decreased PCa parasitisation of the niche. Moreover, the authors were able to mobilize PCa cells out of the HSC niche by using agents known to cause HSCs to reenter the peripheral circulation. This work has identified three potential mechanisms that might be modulated to minimise metastasis of carcinoma cells into bone tissue, opening new possibilities for therapeutic intervention in metastatic cancer.

Robo4 Guides Grafted Blood Stem Cells to the Bone Marrow

New results from the laboratory of Camilla Forsberg at the Institute for the Biology of Stem Cells, University of Santa Cruz, California are beginning to unravel the mechanisms by which transplanted haematopoietic stem cells (HSCs) localise to the bone marrow niche. HSC transplants are a common treatment for various illnesses including certain blood cancers and their correct localisation is critical to the successful function of grafted cells. In their study, Smith-Berdan et al. investigated the guidance molecule Robo4 and discovered its role as a HSC-specific adhesion molecule by facilitating the adhesion of HSCs to the bone marrow niche. They demonstrate that HSCs lacking Robo4 have reduced capacity to localise within the bone marrow following transplantation, drastically reducing long term reconstitution. They demonstrate that Robo4 exerts its effects in cooperation with the Cxcr4 protein, and that inhibition of both these proteins mediates HSC mobilisation. The identification of putative therapeutic targets in HSC transplantation therapy will no doubt lead to greater success of this strategy by enabling more specific integration of grafted cells.

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