PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Jenny Gimpel jenny.gimpel@kcl.ac.uk 44-020-784-84334 King's College London

An international team led by King's College London and the San Francisco Veteran Affairs Medical Center (SFVAMC) has developed the first lab-grown epidermis the outermost skin layer - with a functional permeability barrier akin to real skin. The new epidermis, grown from human pluripotent stem cells, offers a cost-effective alternative lab model for testing drugs and cosmetics, and could also help to develop new therapies for rare and common skin disorders.

The epidermis, the outermost layer of human skin, forms a protective interface between the body and its external environment, preventing water from escaping and microbes and toxins from entering. Tissue engineers have been unable to grow epidermis with the functional barrier needed for drug testing, and have been further limited in producing an in vitro (lab) model for large-scale drug screening by the number of cells that can be grown from a single skin biopsy sample.

The new study, published in the journal Stem Cell Reports, describes the use of human induced pluripotent stem cells (iPSC) to produce an unlimited supply of pure keratinocytes the predominant cell type in the outermost layer of skin - that closely match keratinocytes generated from human embryonic stem cells (hESC) and primary keratinocytes from skin biopsies. These keratinocytes were then used to manufacture 3D epidermal equivalents in a high-to-low humidity environment to build a functional permeability barrier, which is essential in protecting the body from losing moisture, and preventing the entry of chemicals, toxins and microbes.

A comparison of epidermal equivalents generated from iPSC, hESC and primary human keratinocytes (skin cells) from skin biopsies showed no significant difference in their structural or functional properties compared with the outermost layer of normal human skin.

Dr Theodora Mauro, leader of the SFVAMC team, says: "The ability to obtain an unlimited number of genetically identical units can be used to study a range of conditions where the skin's barrier is defective due to mutations in genes involved in skin barrier formation, such as ichthyosis (dry, flaky skin) or atopic dermatitis. We can use this model to study how the skin barrier develops normally, how the barrier is impaired in different diseases and how we can stimulate its repair and recovery."

Dr Dusko Ilic, leader of the team at King's College London, says: "Our new method can be used to grow much greater quantities of lab-grown human epidermal equivalents, and thus could be scaled up for commercial testing of drugs and cosmetics. Human epidermal equivalents representing different types of skin could also be grown, depending on the source of the stem cells used, and could thus be tailored to study a range of skin conditions and sensitivities in different populations."

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Skin layer grown from human stem cells could replace animals in drug and cosmetics testing

Researchers at Boston Children's Hospital have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew like HSCs, and can give rise to all of the cellular components of the blood like HSCs.

The findings mark a significant step toward one of the most sought-after goals of regenerative medicine: the ability to produce HSCs suitable for hematopoietic stem cell transplantation (HSCT) from other cell types, in particular more mature or differentiated cells.

The research team, led by Derrick J. Rossi, PhD, of Boston Children's Program in Cellular and Molecular Medicine, reported their work today online in the journal Cell.

HSCs are the basic starting material for HSCTs, regardless of their source (bone marrow, umbilical cord blood, peripheral blood). The success of any individual patient's HSCT is tied to the number of HSCs available for transplant: the more cells, the more likely the transplant will take hold. However, HSCs are quite rare.

"HSCs only comprise about one in every 20,000 cells in the bone marrow," says Rossi. "If we could generate autologous HSCs from a patient's other cells, it could be transformative for transplant medicine and for our ability to model diseases of blood development."

In their study, Rossi and his collaborators, including lead author Jonah Riddell, PhD, screened gene expression in 40 different types of blood and blood progenitor cells from mice. From this screen they identified 36 transcription factors -- genes that control when other genes are turned on and off -- that are expressed exclusively in HSCs, not in cells that arise from them.

"Blood cell production invariably goes in one direction: from stem cells, to progenitors, to mature effector cells," Rossi explains. "We wanted to reverse the process and derive HSCs from differentiated blood cells using transcription factors that we found were specific to HSCs."

In a series of mouse transplantation experiments, Rossi's team found that six -- Hlf, Runx1t1, Pbx1, Lmo2, Zfp37 and Prdm5 -- of the 36 factors, plus two additional factors not originally identified in their screen -- Mycn and Meis1 -- were sufficient to robustly reprogram two kinds of blood progenitor cells (pro/pre B cells and common myeloid progenitor cells) into iHSCs.

Rossi's team reprogrammed their source cells by exposing them to viruses containing the genes for all eight factors and a molecular switch that turned the factor genes on in the presence of doxycycline. They then transplanted the exposed cells into recipient mice and activated the genes by giving the mice doxycycline.

The resulting iHSCs were capable of generating the entire blood cell repertoire in the transplanted mice, showing that they had gained the ability to differentiate into all blood lineages. Stem cells collected from those recipients were themselves capable of reconstituting the blood of secondary transplant recipients, proving that the eight-factor cocktail could instill the capacity for self-renewal -- a hallmark property of HSCs.

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Blood cells reprogrammed into blood stem cells in mice

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Irene Sege irene.sege@childrens.harvard.edu 617-919-3110 Boston Children's Hospital

BOSTON (April 24, 2014)Researchers at Boston Children's Hospital have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew like HSCs, and can give rise to all of the cellular components of the blood like HSCs.

The findings mark a significant step toward one of the most sought-after goals of regenerative medicine: the ability to produce HSCs suitable for hematopoietic stem cell transplantation (HSCT) from other cell types, in particular more mature or differentiated cells.

The research team, led by Derrick J. Rossi, PhD, of Boston Children's Program in Cellular and Molecular Medicine, reported their work today online in the journal Cell.

HSCs are the basic starting material for HSCTs, regardless of their source (bone marrow, umbilical cord blood, peripheral blood). The success of any individual patient's HSCT is tied to the number of HSCs available for transplant: the more cells, the more likely the transplant will take hold. However, HSCs are quite rare.

"HSCs only comprise about one in every 20,000 cells in the bone marrow," says Rossi. "If we could generate autologous HSCs from a patient's other cells, it could be transformative for transplant medicine and for our ability to model diseases of blood development."

In their study, Rossi and his collaborators, including lead author Jonah Riddell, PhD, screened gene expression in 40 different types of blood and blood progenitor cells from mice. From this screen they identified 36 transcription factorsgenes that control when other genes are turned on and offthat are expressed exclusively in HSCs, not in cells that arise from them.

"Blood cell production invariably goes in one direction: from stem cells, to progenitors, to mature effector cells," Rossi explains. "We wanted to reverse the process and derive HSCs from differentiated blood cells using transcription factors that we found were specific to HSCs."

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Scientists reprogram blood cells into blood stem cells in mice