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Fulltext Susceptibility of Human Oral Squamous Cell Carcinoma (OSCC) H103 and H376 cell lines to Retroviral OSKM mediated reprogramming

Verusingam ND, Yeap SK, Ky H, Paterson IC, Khoo SP, Cheong SK, et al.

PeerJ, 2017;5:e3174.
PMID: 28417059 DOI: 10.7717/peerj.3174

Although numbers of cancer cell lines have been shown to be successfully reprogrammed into induced pluripotent stem cells (iPSCs), reprogramming Oral Squamous Cell Carcinoma (OSCC) to pluripotency in relation to its cancer cell type and the expression pattern of pluripotent genes under later passage remain unexplored. In our study, we reprogrammed and characterised H103 and H376 oral squamous carcinoma cells using retroviral OSKM mediated method. Reprogrammed cells were characterized for their embryonic stem cells (ESCs) like morphology, pluripotent gene expression via quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence staining, embryoid bodies (EB) formation and directed differentiation capacity. Reprogrammed H103 (Rep-H103) exhibited similar ESCs morphologies with flatten cells and clear borders on feeder layer. Reprogrammed H376 (Rep-H376) did not show ESCs morphologies but grow with a disorganized morphology. Critical pluripotency genes Oct4, Sox2 and Nanog were expressed higher in Rep-H103 against the parental counterpart from passage 5 to passage 10. As for Rep-H376, Nanog expression against its parental counterpart showed a significant decrease at passage 5 and although increased in passage 10, the level of expression was similar to the parental cells. Rep-H103 exhibited pluripotent signals (Oct4, Sox2, Nanog and Tra-1-60) and could form EB with the presence of three germ layers markers. Rep-H103 displayed differentiation capacity into adipocytes and osteocytes. The OSCC cell line H103 which was able to be reprogrammed into an iPSC like state showed high expression of Oct4, Sox2 and Nanog at late passage and may provide a potential iPSC model to study multi-stage oncogenesis in OSCC.

Matched MeSH terms: Induced Pluripotent Stem Cells
Fulltext Stem cells research: therapeutic potentials and ethical issues from Islamic perspective

Che Anuar Che Mohamad, Abdurezak Abdullahi Hashi

International Medical Journal Malaysia, 2018;17(101):65-69.
MyJurnal

The advancement in human stem cell research has promised a viable alternative treatment for a range of ‘incurable diseases’ such as neurological diseases. To date, several studies have documented substantial evidences on the therapeutic properties of stem cells in promoting repair in different diseases including common neurological disorders i.e. ischaemic stroke and spinal cord injury. However, the progress of stem cell research has been surrounded by ethical issues which largely due to the usage of human embryos as one of the sources. These embryonic stem cells which originally derived from human embryo of aborted foetus or already existing human embryonic stem cells (hESCs) lines, has sparked an intense moral and religious argument among people of various faith, including Muslim community. From the therapeutic point of view, amongst the currently available stem cells, hESCs show the greatest potential for the broadest range of cell replacement therapies and are regarded as the most commercially viable. This review focuses on the major ethical issues, particularly to Muslim community, related to human embryonic stem cells research with special emphasis on the moral status of the embryo and the beginning of life according to the Islamic ethics and rulings. In this paper, we also discuss some ethical positions towards embryonic stem cell research in the Islamic world, including official regulations existing in some Muslim countries. We examine the justification and the necessity on the usage of hESCs following the newly discovered Induced Pluripotent Stem Cells (IPSCs) in the laboratory. In addition, we supplement the discussions with the general views and positions from the other two Abrahamic religions i.e. Christianity and Judaism.

Matched MeSH terms: Induced Pluripotent Stem Cells
Generation of a MLL-AF9-specific stem cell model of acute monocytic leukemia

Chiew MY, Boo NY, Voon K, Cheong SK, Leong PP

Leuk Lymphoma, 2017 01;58(1):162-170.
PMID: 27185517

Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia (AML), affects mostly young children and has poor prognosis. The mechanisms of treatment failure of AML-M5 are still unclear. In this study, we generated iPSC from THP-1 cells from a patient with AML-M5, using retroviruses encoding the pluripotency-associated genes (OCT3/4, SOX2, KLF4 and c-MYC). These AML-M5-derived iPSC showed features similar with those of human embryonic stem cells in terms of the morphology, gene expression, protein/antigen expression and differentiation capability. Parental-specific markers were down-regulated in these AML-M5-derived iPSCs. Expression of MLL-AF9 fusion gene (previously identified to be associated with pathogenesis of AML-M5) was observed in all iPSC clones as well as parental cells. We conclude that AML-M5-specific iPSC clones have been successfully developed. This disease model may provide a novel approach for future study of pathogenesis and therapeutic intervention of AML-M5.

Matched MeSH terms: Induced Pluripotent Stem Cells/metabolism
Fulltext Therapeutic effects of conditioned - DPBS from amniotic stem cells on lactating cow mastitis

Ting WJ, Shaw SW, Hii LY, Lin TY, Chang SC, Liu KY, et al.

Taiwan J Obstet Gynecol, 2020 Jul;59(4):520-526.
PMID: 32653123 DOI: 10.1016/j.tjog.2020.05.009

OBJECTIVE: Bovine mastitis results in economic loss due to decrease in milk production. Antibiotic ointments are commonly used for treating. However, residue and anti-microbial resistance warranted attention progressively. Fortunately, stem cell anti-inflammatory properties and paracrine expression of cytokines accelerates wound healing and suppresses inflammatory reactions in mastitis. The objective of this study is to use the conditioned-Dulbecco's pluripotent stem cells (DPBS) from amniotic membrane stem cells (AMSCs) in treating bovine mastitis.
MATERIALS AND METHODS: The cows with mastitis were divided into two groups. In antibiotic control group, the cows were given tetraneomycin ointment. In conditioned-DPBS of AMSCs treatment group, amniotic membrane was collected for AMSCs after delivery. With expression of surface antigen and potential of tri-linage differentiation, AMSCs were injected into mammary glands. Then, milk was sampled every three days to monitor the effect of both treatments. The quality of milk was measured with pH, titratable acidity, free calcium ions and somatic cell count.
RESULTS: Our results demonstrated the Bovine AMSCs expressed CD44, low levels of CD4 and no CD105. Bovine AMSCs demonstrated the differentiation capability in the tri-cell lineages. Mastitis treatment with conditioned-DPBS from AMSCs (experimental group) and conventional antibiotics (control group) showed insignificant difference in pH value and titratable acidity. The level of ionic calcium concentration in the conditioned-DPBS group decreased from 3rd day to 12th day, while the level in the antibiotic group decreased from 0 day to 12th day. The somatic cell number was similar in both groups, which meet the standard of Taiwan milk collection.
CONCLUSION: In conclusion, conditioned-DPBS from bovine AMSCs has the therapeutic potential to treat bovine mastitis and may replace antibiotics therapy in the future.

Matched MeSH terms: Pluripotent Stem Cells
Fulltext Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro

Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G, Wu T, et al.

Nat Commun, 2021 08 17;12(1):4997.
PMID: 34404774 DOI: 10.1038/s41467-021-24921-z

Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.

Matched MeSH terms: Induced Pluripotent Stem Cells
Fulltext Tumor Necrosis Factor-Alpha Exacerbates Viral Entry in SARS-CoV2-Infected iPSC-Derived Cardiomyocytes

Lee CY, Huang CH, Rastegari E, Rengganaten V, Liu PC, Tsai PH, et al.

Int J Mol Sci, 2021 Sep 13;22(18).
PMID: 34576032 DOI: 10.3390/ijms22189869

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.

Matched MeSH terms: Induced Pluripotent Stem Cells
Fulltext Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al.

Blood, 2020 Aug 27;136(9):1055-1066.
PMID: 32518946 DOI: 10.1182/blood.2020005844

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Matched MeSH terms: Induced Pluripotent Stem Cells/pathology