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Haematopoetic Stem Cells

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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.

Stem Cell Cures for HIV?

By Stuart P. Atkinson

UNAIDS (Joint United Nations Programme on HIV and AIDS) estimated that at the end of 2009 33.3 million people were living with HIV, and that in the same year there had been 1.8 million AIDS-related deaths and 2.6 million new infections (UN Millennium Goals report 2010). The benefits of anti-retroviral therapy (ART) have been demonstrated in some patients, however, resistance can develop, therapy is expensive (meaning that the vast majority of sufferers cannot have access) and multiple organ toxicity occurs with long-term use. Therefore, a safer and more cost effective therapy is clearly required. There have been reported cases of patients living with long-term HIV infection without progression to AIDS and in other cases patients seem to have some degree of immunity when exposed to the virus – both scenarios suggest a possible genetic influence on an individual’s response to HIV infection.

Potential Stem Cell Therapy for HIV Reported

Potential Stem Cell Therapy for HIV Reported

From Nature Biotech

An advance online article from Nature Biotechnology reports the creation of genetically modified human hematopoietic stem/progenitor cells which when injected and engrafted in mice confer some resistance to HIV.   Specifically, Holt et al disrupted CCR5, the major HIV-1 co-receptor using engineered zinc-finger nucleases (ZFNs) and compared to control mice, the mice which received such cells showed significantly lower HIV-1 levels.

The fountain of youth; Choose your partner wisely.

By Carla B. Mellough

The secret to eternal youth has been under pursuit for centuries. But now, results reported in Nature by a group at Harvard University shed new light on just how the ageing process might be co-ordinated across tissues and, astonishingly, that we may be able to reverse it (Mayack et al., 2010).

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