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Fulltext Integrase deficient lentiviral vector: prospects for safe clinical applications

Yew CT, Gurumoorthy N, Nordin F, Tye GJ, Wan Kamarul Zaman WS, Tan JJ, et al.

PeerJ, 2022;10:e13704.
PMID: 35979475 DOI: 10.7717/peerj.13704

HIV-1 derived lentiviral vector is an efficient transporter for delivering desired genetic materials into the targeted cells among many viral vectors. Genetic material transduced by lentiviral vector is integrated into the cell genome to introduce new functions, repair defective cell metabolism, and stimulate certain cell functions. Various measures have been administered in different generations of lentiviral vector systems to reduce the vector's replicating capabilities. Despite numerous demonstrations of an excellent safety profile of integrative lentiviral vectors, the precautionary approach has prompted the development of integrase-deficient versions of these vectors. The generation of integrase-deficient lentiviral vectors by abrogating integrase activity in lentiviral vector systems reduces the rate of transgenes integration into host genomes. With this feature, the integrase-deficient lentiviral vector is advantageous for therapeutic implementation and widens its clinical applications. This short review delineates the biology of HIV-1-erived lentiviral vector, generation of integrase-deficient lentiviral vector, recent studies involving integrase-deficient lentiviral vectors, limitations, and prospects for neoteric clinical use.
Mesenchymal stem cells facilitate cardiac differentiation in Sox2-expressing cardiac C-kit cells in coculture

Leong YY, Ng WH, Umar Fuaad MZ, Ng CT, Ramasamy R, Lim V, et al.

J Cell Biochem, 2019 06;120(6):9104-9116.
PMID: 30548289 DOI: 10.1002/jcb.28186

Stem cell therapy offers hope to reconstitute injured myocardium and salvage heart from failing. A recent approach using combinations of derived Cardiac-derived c-kit expressing cells (CCs) and mesenchymal stem cells (MSCs) in transplantation improved infarcted hearts with a greater functional outcome, but the effects of MSCs on CCs remain to be elucidated. We used a novel two-step protocol to clonogenically amplify colony forming c-kit expressing cells from 4- to 6-week-old C57BL/6N mice. This method yielded highly proliferative and clonogenic CCs with an average population doubling time of 17.2 ± 0.2, of which 80% were at the G1 phase. We identified two distinctly different CC populations based on its Sox2 expression, which was found to inversely related to their nkx2.5 and gata4 expression. To study CCs after MSC coculture, we developed micron-sized particles of iron oxide-based magnetic reisolation method to separate CCs from MSCs for subsequent analysis. Through validation using the sex and species mismatch CC-MSC coculture method, we confirmed that the purity of the reisolated cells was greater than 85%. In coculture experiment, we found that MSCs prominently enhanced Ctni and Mef2c expressions in Sox2 pos CCs after the induction of cardiac differentiation, and the level was higher than that of conditioned medium Sox2 pos CCs. However, these effects were not found in Sox2 neg CCs. Immunofluorescence labeling confirmed the presence of cardiac-like cells within Sox2 pos CCs after differentiation, identified by its cardiac troponin I and α-sarcomeric actinin expressions. In conclusion, this study shows that MSCs enhance CC differentiation toward cardiac myocytes. This enhancement is dependent on CC stemness state, which is determined by Sox2 expression.
Fulltext Cytoprotective Role of Omentin Against Oxidative Stress-Induced Vascular Endothelial Cells Injury

Binti Kamaruddin NA, Fong LY, Tan JJ, Abdullah MNH, Singh Cheema M, Bin Yakop F, et al.

Molecules, 2020 May 29;25(11).
PMID: 32485974 DOI: 10.3390/molecules25112534

Endothelial cell injury caused by reactive oxygen species (ROS) plays a critical role in the pathogenesis of cardiovascular diseases. Omentin, an adipocytokine that is abundantly expressed in visceral fat tissue, has been reported to possess anti-inflammatory and antidiabetic properties. However, endothelial protective effects of omentin against oxidative stress remain unclear. This study aimed to evaluate the protective effect of omentin against hydrogen peroxide (H2O2)-induced cell injury in human umbilical vein endothelial cells (HUVECs). Cytotoxicity and cytoprotective effects of omentin were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptotic activity of HUVECs was detected using Annexin-V/PI and Hoechst 33258 staining methods. Antioxidant activity of omentin was evaluated by measuring both reactive oxygen species (ROS) levels and glutathione peroxidase (GPx) activity. No cytotoxicity effect was observed in HUVECs treated with omentin alone at concentrations of 150 to 450 ng/ml. MTT assay showed that omentin significantly prevented the cell death induced by H2O2 (p < 0.001). Hoechst staining and flow cytometry also revealed that omentin markedly prevented H2O2-induced apoptosis. Moreover, omentin not only significantly inhibited ROS production (p < 0.01) but also significantly (p < 0.01) increased GPx activity in HUVECs. In conclusion, our data suggest that omentin may protect HUVECs from injury induced by H2O2.
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.
Fulltext Recapitulating human cardio-pulmonary co-development using simultaneous multilineage differentiation of pluripotent stem cells

Ng WH, Johnston EK, Tan JJ, Bliley JM, Feinberg AW, Stolz DB, et al.

Elife, 2022 01 12;11.
PMID: 35018887 DOI: 10.7554/eLife.67872

The extensive crosstalk between the developing heart and lung is critical to their proper morphogenesis and maturation. However, there remains a lack of models that investigate the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing the simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human-induced pluripotent stem cells (hiPSCs) via temporal specific tuning of WNT and nodal signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (μTs), and expedited alveolar maturation in the presence of cardiac accompaniment. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage μT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect that our multilineage differentiation model will offer an experimentally tractable system for investigating human cardio-pulmonary interaction and tissue boundary formation during embryogenesis.
Fulltext Breast milk from healthy women has higher anti-Candida properties than women with vaginal infections during pregnancy

Nisaa AA, Oon CE, Sreenivasan S, Balakrishnan V, Tan JJ, Teh CS, et al.

Food Sci Biotechnol, 2023 Mar;32(4):471-480.
PMID: 36911325 DOI: 10.1007/s10068-022-01088-x

The aim of this study was to investigate the different immunological and antimicrobial properties of breast milk from women with (W) or without (WO) vaginal yeast infections during pregnancy in 85 lactating women (W, n = 43; WO, n = 42). Concentrations of IL-10, IgA, IgM, IgG, EGF, and TGF-α were similar in both groups. However, breast milk of women aged below 31 years old from the W-group showed higher concentration of EGF than the WO-group (p = 0.031). Breast milk from WO-group exhibited higher anti-Candida properties than W-group, both via growth inhibition and aggregation of yeast cells (p
Intrapericardial Administration of Human Pericardial Fluid Cells Improves Cardiac Functions in Rats with Heart Failure

Xu Y, Zhang X, Fu Z, Dong Y, Yu Y, Liu Y, et al.

Stem Cells Dev, 2024 Nov;33(21-22):616-629.
PMID: 39155804 DOI: 10.1089/scd.2024.0072

Heart failure (HF) is still the main cause of mortality worldwide. This study investigated the characteristics of human pericardial fluid-derived cells (hPFCs) and their effects in treating doxorubicin (DOX)-induced HF rats through intrapericardial injection. hPFCs were isolated from patients who underwent heart transplantation (N = 5). These cells that primarily expressed SCA-1, NANOG, and mesenchymal markers, CD90, CD105, and CD73, were able to form adipocytes, osteoblasts, and cardiomyocytes in vitro. Passage 3 hPFCs (2.5 × 105 cells/heart) were injected into the pericardial cavity of the DOX-injured rat hearts, significantly improving cardiac functions after 4 weeks. The tracked and engrafted red fluorescent protein-tagged hPFCs coexpressed cardiac troponin T and connexin 43 after 4 weeks in the host myocardium. This observation was also coupled with a significant reduction in cardiac fibrosis following hPFC treatment (P < 0.0001 vs. untreated). The elevated inflammatory cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor-α in the DOX-treated hearts were found to be significantly reduced (P < 0.001 vs. untreated), while the regional proangiogenic vascular endothelial growth factor A (VEGFA) level was increased in the hPFC-treated group after 4 weeks (P < 0.05 vs. untreated). hPFCs possess stem cell characteristics and can improve the cardiac functions of DOX-induced HF rats after 4 weeks through pericardial administration. The improvements were attributed to a significant reduction in cardiac fibrosis, inflammation, and elevated regional proangiogenesis factor VEGFA, with evidence of cellular engraftment and differentiation in the host myocardium.
Reprogramming of Expanded Cord Blood-Derived CD34+ Cells from Umbilical Cord-Mesenchymal Stromal Cell Co-Culture to Generate Human-Induced Pluripotent Stem Cells

Roslan FF, Yu Y, Wang M, Mohd Yusof NAN, Ooi GC, Then KL, et al.

Cell Reprogram, 2024 Nov 27.
PMID: 39602209 DOI: 10.1089/cell.2024.0073

Cord blood (CB) is widely stored as a source of hematopoietic stem cells for potential future use, though its application for autologous purposes remains limited. Repurposing CB into human-induced pluripotent stem cells (hiPSCs) can broaden its utility beyond hematological conditions. This study investigated the effects of umbilical cord-mesenchymal stromal cell (UC-MSC) co-culture on CB CD34+ cells and the characteristics of the resulting hiPSCs. CD34+ cells were isolated, expanded in UC-MSC co-culture for 3 days, and reprogrammed into hiPSCs using episomal vectors. Results showed that UC-MSC co-culture significantly increased CD34+ cell numbers (p < 0.0001, n = 6), with a reduced population doubling time of 25.1 ± 2.1 hours compared with the control (p < 0.0004, n = 6). The yield of CD34+ cells was substantially higher in the UC-MSC co-culture group. The hiPSCs exhibited comparable reprogramming efficiency, pluripotency marker expression, trilineage differentiation potential, and genomic stability to CD34+ cells expanded under standard culture conditions. These findings suggest that CD34+ cells from CB, expanded in UC-MSC co-culture, can be reprogrammed into functional hiPSCs without compromising cell quality or genetic stability.
Fulltext Nutrition therapy for critically ill patients across the Asia-Pacific and Middle East regions: A consensus statement

Sioson MS, Martindale R, Abayadeera A, Abouchaleh N, Aditianingsih D, Bhurayanontachai R, et al.

Clin Nutr ESPEN, 2018 04;24:156-164.
PMID: 29576355 DOI: 10.1016/j.clnesp.2017.11.008

BACKGROUND & AIMS: Guidance on managing the nutritional requirements of critically ill patients in the intensive care unit (ICU) has been issued by several international bodies. While these guidelines are consulted in ICUs across the Asia-Pacific and Middle East regions, there is little guidance available that is tailored to the unique healthcare environments and demographics across these regions. Furthermore, the lack of consistent data from randomized controlled clinical trials, reliance on expert consensus, and differing recommendations in international guidelines necessitate further expert guidance on regional best practice when providing nutrition therapy for critically ill patients in ICUs in Asia-Pacific and the Middle East.
METHODS: The Asia-Pacific and Middle East Working Group on Nutrition in the ICU has identified major areas of uncertainty in clinical practice for healthcare professionals providing nutrition therapy in Asia-Pacific and the Middle East and developed a series of consensus statements to guide nutrition therapy in the ICU in these regions.
RESULTS: Accordingly, consensus statements have been provided on nutrition risk assessment and parenteral and enteral feeding strategies in the ICU, monitoring adequacy of, and tolerance to, nutrition in the ICU and institutional processes for nutrition therapy in the ICU. Furthermore, the Working Group has noted areas requiring additional research, including the most appropriate use of hypocaloric feeding in the ICU.
CONCLUSIONS: The objective of the Working Group in formulating these statements is to guide healthcare professionals in practicing appropriate clinical nutrition in the ICU, with a focus on improving quality of care, which will translate into improved patient outcomes.
Metabolic glycan labeling and chemoselective functionalization of native biomaterials

Ren X, Evangelista-Leite D, Wu T, Rajab TK, Moser PT, Kitano K, et al.

Biomaterials, 2018 11;182:127-134.
PMID: 30118980 DOI: 10.1016/j.biomaterials.2018.08.012

Decellularized native extracellular matrix (ECM) biomaterials are widely used in tissue engineering and have reached clinical application as biomesh implants. To enhance their regenerative properties and postimplantation performance, ECM biomaterials could be functionalized via immobilization of bioactive molecules. To facilitate ECM functionalization, we developed a metabolic glycan labeling approach using physiologic pathways to covalently incorporate click-reactive azide ligands into the native ECM of a wide variety of rodent tissues and organs in vivo, and into the ECM of isolated rodent and porcine lungs cultured ex vivo. The incorporated azides within the ECM were preserved after decellularization and served as chemoselective ligands for subsequent bioconjugation via click chemistry. As proof of principle, we generated alkyne-modified heparin, immobilized it onto azide-incorporated acellular lungs, and demonstrated its bioactivity by Antithrombin III immobilization and Factor Xa inhibition. The herein reported metabolic glycan labeling approach represents a novel platform technology for manufacturing click-reactive native ECM biomaterials, thereby enabling efficient and chemoselective functionalization of these materials to facilitate tissue regeneration and repair.
Fulltext Vaginal Infections during Pregnancy Increase Breast Milk Microbiome Alpha Diversity and Alter Taxonomic Composition

Nisaa AA, Oon CE, Sreenivasan S, Balakrishnan V, Rajendran D, Tan JJ, et al.

Prev Nutr Food Sci, 2023 Mar 31;28(1):1-9.
PMID: 37066035 DOI: 10.3746/pnf.2023.28.1.1

We previously reported that breast milk from women with (W) or without (WO) vaginal yeast infection during pregnancy differs in its immunological and antimicrobial properties, especially against pathogenic vaginal Candida sp.. Here, we investigated the differences in microbiota profiles of breast milk from these groups. Seventy-two breast milk samples were collected from lactating mothers (W, n=37; WO, n=35). The DNA of bacteria was extracted from each breast milk sample for microbiota profiling by 16S rRNA gene sequencing. Breast milk from the W-group exhibited higher alpha diversity than that from the WO-group across different taxonomic levels of class (P=0.015), order (P=0.011), family (P=0.020), and genus (P=0.030). Compositional differences between groups as determined via beta diversity showed marginal differences at taxonomic levels of phylum (P=0.087), family (P=0.064), and genus (P=0.067). The W-group showed higher abundances of families Moraxellaceae (P=0.010) and Xanthomonadaceae (P=0.008), and their genera Acinetobacter (P=0.015), Enhydrobacter (P=0.015), and Stenotrophomonas (P=0.007). Meanwhile, the WO-group showed higher abundances of genus Staphylococcus (P=0.046) and species Streptococcus infantis (P=0.025). This study shows that, although breast milk composition is affected by vaginal infection during pregnancy, this may not pose a threat to infant growth and development.

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