The Living Dead (of the iPSC world): Autopsy donor-derived iPSCs
From Neuroscience Letters
Commentary by Carla B. Mellough
In vitro disease modelling approaches largely involve the use of immortalised cell lines that have been genetically altered in order to induce a disease phenotype. While these systems provide valuable information, such models are unable to represent complex human disease aetiology and are therefore not always physiologically relevant. As induced pluripotent stem cells (iPSCs) retain the genetic profile of the somatic donor cell of origin, iPSCs represent an important additional option for disease modelling in vitro. This approach offers many advantages over previous methods, for example the non-invasive study of neurological or neurodegenerative conditions that are ordinarily impossible premortem, or certainly risk some cognitive or functional impairment if undertaken. Yet one major complication of this approach is that the effectiveness of iPSC disease models in vitro relies entirely upon the accuracy of the premortem diagnosis. In fact, most premortem diagnoses of neurological disease made from clinical criteria are not definite and can only be confirmed following postmortem histopathological analysis, so it would be advantageous if we could generate iPSC from post-mortem tissues. A study from Arizona, USA, by Hjelm et al.1 has demonstrated that iPSCs can indeed be generated from autopsy-derived fibroblasts. Creating iPSC lines from dead human tissues may be viewed by some as a little macabre, hence our reference to the 1974 film “The living dead” in the title, but in reality this development opens another avenue for iPSC-based disease modelling following a definite postmortem diagnosis.
Skeletogenic phenotype of human Marfan ESCs faithfully phenocopied by patient-specific iPSCs
From PNAS
By Stuart P. Atkinson
Marfan syndrome (MFS) is a heritable dominant disorder caused by mutations in the FBN1 gene (Dietz et al and Pereira et al) affecting the skeletal, ocular and cardiovascular systems. FBN1 itself is an extracellular matrix (ECM) glycoprotein and although the molecular pathogenesis was originally thought to be due to resultant defects in the ECM, other results suggested that altered TGFβ signalling may be the main cause of pathogenic abnormalities in MFS (Dietz et al and Liu et al). Now, researchers from the laboratory of Michael Longlaker at the Standford University School of Medicine have succeeded in deriving FBN1 mutant human embryonic stem cells (hESCs) and also producing human induced pluripotent stem cells (hiPSCs) from FBN1 mutant fibroblasts (Quarto et al). Importantly, during this study of FBN1 mutations in hESCs, they also found that mutant hESCs and hiPSCs give rise to differentiated cells which demonstrate the same phenotype, demonstrating that iPSCs can provide complementary and powerful tools to gain further insights into human molecular pathogenesis.
Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells
From PNAS
By Stuart P. Atkinson
Tumour initiating stem cells (TISCs) are rare, highly malignant cells identified within diverse tumor types that share important similarities with embryonic stem cells (ESCs) (Clark and Fuller, Visvader and Lindeman and Clevers) including the mis-regulated expression of OCT4, SOX2, and NANOG (Chen et al and Kim et al). Studies have begun to give insight into the events behind TISC function, such as the loss of function of the type II TGF-β receptor and excessive activation of the IL-6 cytokine-signaling pathway, including the downstream effector STAT3 human hepatocellular carcinoma (HCC) (Baek et al and Tang et al). In a mouse model of HCC, isolation of highly tumourigenic CD133+/Nanog+ liver TISCs (Machida et al) on the basis of cell-surface receptors has suggested that identification of TISC-associated cell surface receptor expression and associated signal transduction pathways may be important for TISC function. Therefore researchers from the laboratories of Douglas Edmund Feldman and Keigo Machida at the University of Southern California sought to study this hypothesis and report that the leptin receptor (OB-R or Lepr), a transmembrane receptor for the adipocyte-derived peptide hormone leptin, is important for the tumourigenic nature of TISCs and also for the pluripotent nature of ESCs and induced pluripotent stem cells (iPSCs) (Feldman et al).
ESCs JNK their way to Neurogenesis – A chromatin-modifying function of JNK during stem cell differentiation
From Nature Genetics
By Stuart P. Atkinson
c-Jun N-terminal kinases (JNKs) are a subgroup of mitogen-activated protein kinases (MAPKs), and have been suggested to mediate transcriptional changes through their downstream effectors (Bogoyevitch and Kobe and Pearson et al), such as AP-1 (a heterodimeric transcription factor composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families). Additionally, some signal-activated kinases have been suggested to bind to chromatin at certain genes. Mouse embryonic stem cells (mESCs) lacking JNK1 (Mapk8) show dysregulation of lineage-commitment genes (Amura et al) and fail to undergo neuronal differentiation, suggesting a vital role for JNK1 in the lineage specific differentiation of mESCs. Researchers from the group of Christian Beisel from the Eidgenössische Technische Hochschule (ETH) Zürich, Basel, Switzerland have now undertaken a detailed analysis of the JNK proteins in mESCs during self renewal and differentiation, finding that gene specific JNK-mediated chromatin modification is critical for neuronal differentiation (Tiwari et al).
Emi1 for a Spin? – Cell cycle adaptations of embryonic stem cells
From PNAS
By Stuart P. Atkinson
Mouse embryonic stem cells (mESCs) have a remarkably short G1 and G2 phase, which in somatic cells is determined by Cdk activity alongside other cell-cycle related proteins which fluctuate during the cell cycle due to APC/C mediated degradation. APC/C is a large multi-subunit E3 ubiquitin ligase, which can be activated by Cdc20 and Cdh1 interaction at the end of mitosis and inactivated by Emi1 (or Fbxo5) and degradation of Cdh1 just before S-phase. Inhibition of Cdk activity in G1 phase allows the replication factors Cdt1 and Cdc6 to recruit Mcm proteins onto chromatin, form pre-replicative complexes (pre-RCs) and license DNA for replication. Previous studies found that in mESCs APC/C substrates were constant and Cdk activity high throughout the mESC cell cycle (White et al, Fujii-Yamamoto et al and Yang et al). However, the careful re-appraisal of protein levels and activity in mESC by researchers from the laboratory of Marc W. Kirschner have uncovered oscillations in APC/C substrate levels and Cdk activity which, alongside other key findings, promote the abbreviated cell cycle of mESCs (Ballabeni et al).
Stem Cell Transplant Down to a T - Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFNγ and TNFα
From Nature Medicine
By Stuart P. Atkinson
Bone marrow mesenchymal stem cells (BMMSCs) are multipotent adult stem cells which are capable of differentiating into various cell types (osteoblasts, adipocytes and chondrocytes (Friedenstein et al, Pittinger et al and Prockop)) and their regenerative capabilities shown to be of clinical importance in the treatment of bone and bone-associated tissue disease (Caplan, García-Gómez et al, Tasso et al and Bueno and Glowacki). Further, BMMSCs have been shown to interact with immune cells to aid bone regeneration but the specific function of recipient immune cells has not been assessed. Now, researchers from the laboratory of Songtao Shi at the University of Southern California, USA, have found that recipient immune cells, specifically T cells, govern BMMSC-based tissue regeneration using an established in vivo BMMSC implantation system (Liu et al).
Hosting the brightest young stem cell biologists in the Hawk’s Nest: the 7th Young Investigator Stem Cell Award symposia, Serbia 2011
On a beautiful Saturday morning of the 15th of October, the fourth largest city of Serbia, Kragujevac welcomed a large number of international stem cell scientists to celebrate the 7th Young Investigator Award (YIA) of Stem Cells for 2011. The name of the city is derived from the Serbian word “kraguj” – or “Hawk” and the name Kragujevac translates as, “the Hawk’s nest”. This is a beautiful region of Serbia, made all the more stunning by the colours of Autumn but the famous Serbian hospitality and their delicious traditional food and drink made this a truly memorable meeting place. Kragujevac was the first capital of modern Serbia and has been known for a while as the country’s biggest auto manufacturer but in the last ten years the city has seen major academic and scientific developments so that the Medical Faculty of Kragujevac University figures as one the top 5 five scientific institutions in Serbia. It is no wonder that both the Medical Faculty and the city of Kragujevac were the main driving force and sponsors for such a prestigious annual event organised by the “Stem Cells” journal.
Stem Cells Fraud Scheme in U.S. Leads to Arrests
Four people were recently indicted on federal charges in the United States for selling unapproved stem cell treatments and other biological products to seriously ill patients. The patients were falsely told that the treatments were approved by the U.S. Food and Drug Administration, according to the indictment.
Francisco Morales, Larry Stowe, Jesus Alberto Ramon and Dr. Vincent Dammai are charged with collecting in excess of $1.5 million from people suffering from Lou Gehrig's disease, Parkinson's, muscular dystrophy and cancer over a period from 2007 to 2010. Ramon, a licensed midwife and owner of the Maternity Care Clinic in Del Rio, Mexico, allegedly sold the umbilical cords of women giving birth at his clinic to Global Laboratories LLC, in Scottsdale, Ariz., which forwarded them to Dammai, an assistant professor at the University of South Carolina's medical school. Dammai harvested the stem cells for Global using university facilities. He did this without FDA or university knowledge or approval, the indictment says.
