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PRC2 Complexes with JARID2, and esPRC2p48 in ES Cells to Modulate ES Cell Pluripotency and Somatic Cell Reprogramming

From the February 2011 Issue of Stem Cells

Paper commentary by Stuart Atkinson

Recently, the Polycomb repressor complex PRC2 and its known constituents (notably Jarid2 and Pcl2 (or Mtf2)) have received an appraisal of their roles in the pluripotent nature and differentiation of embryonic stem cells (ESC) (Reviewed in Margueron and Reinberg). PRC2 is known to have methyltransferase activity targeted towards lysine 27 of histone H3 (K27 H3) catalysed by Ezh2 which initiates epigenetic silencing of genes, maintained by the subsequent binding of the methylated K27 H3 by the CBX subunits in the PRC1 multi-subunit complex. This mechanism of regulation is vitally important in the silencing of non-specific lineage associated gene expression in development, and as demonstrated recently, in ESCs. A new study (Zhang et al.) from the laboratories of Tim M. Townes and Hengbin Wang at the Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham in the February edition of Stem Cells, reports similar findings to previous studies (see further reading below) by identifying Jarid2 and Mtf2 (Pcl2) as members of the PRC2 complex in mouse ESCs (mESCs). However they also go on to describe a novel mESC specific subunit, esPRC2p48 (Hypothetical protein E130012A19Rik) which is demonstrated to be as critical to proper PRC2 function as the other subunits.

PRC2 Complexes with JARID2, and esPRC2p48 in ES Cells to Modulate ES Cell Pluripotency and Somatic Cell Reprogramming

From the February 2011 Issue of Stem Cells

Paper commentary by Stuart Atkinson

Recently, the Polycomb repressor complex PRC2 and its known constituents (notably Jarid2 and Pcl2 (or Mtf2)) have received an appraisal of their roles in the pluripotent nature and differentiation of embryonic stem cells (ESC) (Reviewed in Margueron and Reinberg). PRC2 is known to have methyltransferase activity targeted towards lysine 27 of histone H3 (K27 H3) catalysed by Ezh2 which initiates epigenetic silencing of genes, maintained by the subsequent binding of the methylated K27 H3 by the CBX subunits in the PRC1 multi-subunit complex. This mechanism of regulation is vitally important in the silencing of non-specific lineage associated gene expression in development, and as demonstrated recently, in ESCs. A new study (Zhang et al.) from the laboratories of Tim M. Townes and Hengbin Wang at the Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham in the February edition of Stem Cells, reports similar findings to previous studies (see further reading below) by identifying Jarid2 and Mtf2 (Pcl2) as members of the PRC2 complex in mouse ESCs (mESCs). However they also go on to describe a novel mESC specific subunit, esPRC2p48 (Hypothetical protein E130012A19Rik) which is demonstrated to be as critical to proper PRC2 function as the other subunits.

Osteoblasts Derived from Induced Pluripotent Stem Cells form Calcified Structures in Scaffolds both in vitro and in vitro

From the February 2011 Issue of Stem Cells

Paper commentary by Stuart Atkinson

The correct and efficient differentiation of pluripotent cell types to clinically relevant cell types is a major common goal in stem cell biology. Recent advances in induced pluripotent stem cell (iPSC) technologies have put the prize of patient-specific stem cells for autologous cellular therapy firmly within biomedical sciences’ grasp. The regeneration of the musculoskeletal system is one such system in which iPSC technology could have a great impact. Current strategies involve bone autografts and autologous transplantation of mesenchymal stem cells (MSCs) from the bone marrow, but both have severe limitations. Bone autografts are invasive and have a high morbidity rate (Arrington et al.) and while autologous MSCs exhibit great potential for musculoskeletal regeneration, their proliferative potential decreases greatly with age, perhaps limiting this type of therapy to younger patients (Stenderup et al.). The potential of iPSCs to be differentiated to MSCs has been demonstrated previously (Lian et al.), and indeed these iPSC-derived MSCs were shown to contribute to tissue regeneration more than bone marrow-derived MSCs in a rodent model of hind limb ischemia. Moreover, the MSCs generated in this particular study were able to proliferate for 120 population doublings with no observable karyotypic abnormalities, overall making iPSC-derived MSCs a very attractive proposition. Now,Bilousova et al. from the laboratory of Susan M. Majka at the University of Colorado, Denver in the forthcoming edition of Stem Cells extend these previous studies to further evaluate the potential of iPSCs for use in the regeneration of the musculoskeletal system.

Osteoblasts Derived from Induced Pluripotent Stem Cells form Calcified Structures in Scaffolds both in vitro and in vitro

From the February 2011 Issue of Stem Cells

Paper commentary by Stuart Atkinson

The correct and efficient differentiation of pluripotent cell types to clinically relevant cell types is a major common goal in stem cell biology. Recent advances in induced pluripotent stem cell (iPSC) technologies have put the prize of patient-specific stem cells for autologous cellular therapy firmly within biomedical sciences’ grasp. The regeneration of the musculoskeletal system is one such system in which iPSC technology could have a great impact. Current strategies involve bone autografts and autologous transplantation of mesenchymal stem cells (MSCs) from the bone marrow, but both have severe limitations. Bone autografts are invasive and have a high morbidity rate (Arrington et al.) and while autologous MSCs exhibit great potential for musculoskeletal regeneration, their proliferative potential decreases greatly with age, perhaps limiting this type of therapy to younger patients (Stenderup et al.). The potential of iPSCs to be differentiated to MSCs has been demonstrated previously (Lian et al.), and indeed these iPSC-derived MSCs were shown to contribute to tissue regeneration more than bone marrow-derived MSCs in a rodent model of hind limb ischemia. Moreover, the MSCs generated in this particular study were able to proliferate for 120 population doublings with no observable karyotypic abnormalities, overall making iPSC-derived MSCs a very attractive proposition. Now,Bilousova et al. from the laboratory of Susan M. Majka at the University of Colorado, Denver in the forthcoming edition of Stem Cells extend these previous studies to further evaluate the potential of iPSCs for use in the regeneration of the musculoskeletal system.

2010 Winner - Cinzia Rota

Law, Ethics, Religion, and Clinical Translation in the 21st Century  – A Conversation with Cinzia Rota

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Another Blow to the iPSC Field?

From Nature

A recent report in Nature (Lister et al.) has suggested that human induced pluripotent stem cells (iPSC), the great hope for personalised cellular therapy, are not as similar to embryonic stem cells (ESCs) as hoped, and that this may affect their use as a replacement for ESC in disease modelling and cellular therapy.

Centromeric and telomeric regions in iPSCs were found to maintain a DNA methylation state similar to that of their cell of origin, and were further linked to changes in methylation of histone H3 and transcriptional activity. Some regions of difference were shared between the multiple iPSC lines studied, suggesting that certain loci may be “inherently susceptible to aberrant methylation” while other regions of difference were iPSC specific, also suggesting “a stochastic element to reprogramming”. It was also observed that these differences are transmitted through differentiation of iPSC towards a trophoblastic lineage.

Another Blow to the iPSC Field?

From Nature

A recent report in Nature (Lister et al.) has suggested that human induced pluripotent stem cells (iPSC), the great hope for personalised cellular therapy, are not as similar to embryonic stem cells (ESCs) as hoped, and that this may affect their use as a replacement for ESC in disease modelling and cellular therapy.

Centromeric and telomeric regions in iPSCs were found to maintain a DNA methylation state similar to that of their cell of origin, and were further linked to changes in methylation of histone H3 and transcriptional activity. Some regions of difference were shared between the multiple iPSC lines studied, suggesting that certain loci may be “inherently susceptible to aberrant methylation” while other regions of difference were iPSC specific, also suggesting “a stochastic element to reprogramming”. It was also observed that these differences are transmitted through differentiation of iPSC towards a trophoblastic lineage.

Hearing with your Nose: How Nasal Stem Cells Could Tackle Childhood Hearing Problems

Durham, NC – Stem Cell scientists in Australia have found that patients suffering from hearing problems which began during infancy and childhood could benefit from a transplant of stem cells from their nose. The research, published today in STEM CELLS, reveals that mucosa-derived stem cells can help preserve hearing function during the early-onset of sensorineural hearing loss.

Sensorineural hearing loss is caused by the loss of sensory cells or neurons in the cochlea, the sensory organ of the inner ear responsible for hearing. The condition can have genetic causes, often arising during infancy and childhood, hindering cognitive development and leading to speech and language problems.

Reprogramming: what’s next?

A commentary on a recent mRNA reprogramming paper by Loring Lab Researchers:
Trevor Leonardo, Ileana Slavin and Ha Tran

Human embryonic stem cells (hESCs) have great potential in the fields of basic research, disease modeling and regenerative medicine with their unique property of unlimited self-renewal and ability to differentiate into any cell type in the body. However, the methods used to obtain hESCs include destroying an embryo and thus pose major ethical concerns. Researchers have recently made great breakthroughs in methods to genetically reprogram differentiated adult cells into a stem cell-like state. These induced pluripotent stem cells (iPSCs) can be made from any individual, from a bit of skin or a few strands of hair, and so do not pose the same ethical concerns as hESCs.

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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