Department of Regenerative Medicine and Translational Science, Calcutta School of Tropical Medicine, India
There are about 100 million births in the world annually at a conservative estimate. In India, there are over 20 million births per annum, which means that over 20 million placentas are discarded every year as waste. One of the products of the placenta is cord blood; it has immense potentials. An estimated 8,785,000 Litres of cord blood is produced globally per year if an average of 84-90 ml/placenta collection is assumed. Our group of medical scientists and clinicians transfused ABO screened and HLA matched randomized fetal blood in cases of anemia resulting from malaria, diabetes, thalassemia, leprosy, rheumatoid arthritis, tuberculosis, malignancy, AIDS, and found it not only to be safe but perhaps providing additional benefits that need further study.
In parts of the world where research is ongoing, a microscopic section of cord bloodʼs mononuclear cells (0.01% nucleated cells) is used for transplantation purposes, while the rest, i.e., 99.99% is discarded. But the discarded part has many potential uses. Cord blood is free from infection, hypoantigenic in nature, has an altered metabolic profile, is enriched with growth factors and cytokine filled plasma and has a potentially higher oxygen carrying capacity than adult blood.
The blood volume of a fetus at term is around 80-85 ml/kg. The placental vessel at term contains approximately 150 ml of cord blood. Cord blood contains three types of hemoglobin, HbF (major fraction); HbA (15-40%) and HbA2 (trace amounts). HbF, which is the major component, has a greater oxygen binding affinity than HbA. Our group of medical scientists and clinicians conducted over 1260 cord blood transfusions with safe outcomes in all cases, as indicated in our published studies, from 1999 till date (followup) in children and adults for various indications. Not a single case of immediate or delayed immunological or non immunological reaction was reported.
Dr. Niranjan Bhattacharya holds a MD in Obstetrics and Gynaecology, MS in General Surgery and a D.Sc. in Developmental Immunology. His principal specializations are cell and tissue therapy. Has presented Invited lectures in several international universities and institutions. Has published widely in international and national journals on cord blood and regenerative medicine; is the co-editor of five books on the subject published by Springer. Currently, Chair Professor and Head of the Department, Regenerative Medicine and Translational Science, and Director General, first Public Cord Blood Bank in India, Calcutta School of Tropical Medicine, Kolkata. Cited among top five global cord blood influencers by BioInformant.
1Cardiff Institute of Tissue Engineering & Repair (CITER), Cardiff University, UK
2Drug Discovery/Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Australia
3QBiotics Ltd., Australia
4Welsh Kidney Research Unit, Cardiff Institute of Tissue Engineering & Repair (CITER), Cardiff University, UK
Dysfunctional wound repair can cause significantly delayed re-epithelialization, leading to non-healing chronic wounds and burns. Management of chronic wounds and burns, poses significant challenges to Healthcare Services worldwide confounded by acceptance that existing therapies are largely unsatisfactory. We are addressing such inadequacies, by evaluating the novel healing properties of epoxy-tigliane compounds, EBC-46 and EBC-211, isolated from seeds of the Fontainʼs Blushwood Tree indigenous to Queenslandʼs tropical rainforest. Our industrial partner, QBiotics Ltd., is developing EBC-46 as an anti-cancer drug. In addition to its anti-cancer properties, EBC-46 stimulates exceptional healing following tumour destruction, manifested as enhanced wound re-epithelialisation, closure and minimal scarring. This work describes epoxy-tigliane effects on keratinocyte wound healing responses and their underlying mechanisms of action.
Immortalized human epidermal keratinocytes (HACATs) were treated with EBC-46 or EBC-211 (0-10µg/mL). Cell cycle progression/proliferation were assessed by FACS analysis and MTT assay. HACAT migration was assessed using in vitro scratch wounds/Time-Lapse Microscopy.Global gene expression changes induced by epoxy-tiglianes were quantified by Microarrays, with differentially expressed genes confirmed by protein level analysis. As epoxy-tiglianes mediate responses via classical protein kinase (PKC) activation, mechanistic studies were performed with BIM-1 (pan-PKC), Gö6976 (classical-PKC) and LY317615 (PKC-βI/PKC-βII) inhibitors. Western blotting confirmed phospho-PKC activation following epoxy-tigliane treatment.
Both epoxy-tiglianes induced significant HACAT cell cycle progression and proliferation at 0.001-10µg/mL. EBC-46 (0.001-0.1µg/mL) and EBC-211 (0.001-10µg/mL) also promoted significant HACAT scratch wound closure. Epoxy-tiglianes significantly up-regulated gene for keratins, positive cell cycle/proliferation regulatory factors and matrix metalloproteinases; and down-regulated genes for other keratins and numerous cytokines, growth factors and chemokines. Enhanced proliferative and migratory responses were significantly abrogated by BIM-1 and Gö6976, although LY317615 exhibited minimal inhibitory effects. PKC activation increased following epoxy-tigliane treatment.
Such findings explain the enhanced re-epithelialization responses in epoxy-tigliane-treated skin; and provide justification for their translational development as novel therapeutics for impaired wound re-epithelialisation.
Dr. Ryan Moseley is a Reader in Tissue Repair and Director of the MSc Programme in Tissue Engineering at Cardiff University, UK. Dr. Moseleyʼs research focusses on the mechanisms underlying dermal and oral wound healing responses during health and disease; and the development of stem cell-, biomaterialand pharmaceutical-based strategies to address impaired healing in these tissues. Dr Moseley has been supported by funding bodies worldwide, including the MRC, NHMRC and Wellcome Trust, culminating in numerous published papers, filed patents with industrial partners in the dermal wound healing sector (Convatec, Systagenix Wound Management, Peplin/LEO Pharma, QBiotics); and many conference prizes.
Department of Chemistry & Biochemistry and Vitalite Health Network, University of Moncton, Georges L-Dumont University Hospital Center, Canada
Upstream translation initiation sites (uAUGs) and open reading frames (uORFs) are post transcriptional regulatory elements found in eukaryotic species, including fungi, plants and mammals. Functional uAUGs initiate translation within the 5 untranslated region (5ʼ UTR), and block a fraction of ribosomes to access the downstream cAUG of the coding region (CDS). Thus, they partially repress translation of the CDS to ensure CDS-encoded proteins do not exceed optimal levels. In addition to their role as translational repressors, some uAUGs initiate translation of short peptides (micropeptides). Innovations in computing, transcriptomics and proteomics have uncovered several uORF-encoded micropeptides. Many of these micropeptides exhibit significant selective constraint in their sequence, suggesting their functional relevance. Indeed, fora few uORF-micropeptides the cellular localization and specific cis- or trans -mediated roleshave been identified, that are different from the role of the downstream CDS-encoded protein. Upstream AUGs/uORFs can be either physiological orintroduced by single nucleotide polymorphisms (SNP) associated with human diseases. While translation of micropeptides from physiological uORFs has been well demonstrated, only three studies have examined translation of microproteins from SNP-introduced uORFs. Overall, the biological relevance of SNP introduced uORFs has been neglected. Lack of knowledge of the biological relevance of SNP introduced uATGs/uORFs-micropeptides prevents the development of related therapeutics.
Dr. Armata is a molecular and cellular neuroscientist, who specializes in dystonia, a heterogenic group of debilitating neurological disorders, affecting both children and adults. Her training and expertise is in the fields of gene expression, transcription factors, functional non-coding mutations, assay development for drug high throughput screenings, and the CRISPR/Cas9 system. She obtained her Ph.D. in Neuroscience at Mount Sinai School of Medicine (2008), followed by a postdoctoral fellowship (2008-2012) at Massachusetts General Hospital and Harvard Medical School, and followed by a Research Faculty I appointment at Florida State University (2013-2016). She is currently a senior Research Fellow at the University of Moncton (Canada) studying translational therapeutics for dystonia syndromes and myotonic dystrophy 1. She has recently got an affiliation with the hospital Dr. Georges-L.-Dumont University Hospital Center, Canada.
Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Israel
Modern medicine offers no cure for genetic mitochondrial disorders and the usual treatment is mostly palliative. We developed a novel concept for the treatment of mitochondrial disorders using Cell/Organelle-Directed Protein Replacement Therapy; the delivery of a wild type mitochondrial protein/enzyme directly to its sub-cellular location and into its natural complexes, in the form of a fusion protein. Our approach is to fuse a wild type mitochondrial protein, including the Mitochondrial Targeting Sequence (MTS), with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide], which will lead the protein/enzyme into the cells and their mitochondria, where it will substitute for the mutated endogenous protein.
We tested this novel approach using a number of mitochondrial proteins, implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAD), C6ORF66 (ORF), Frataxin (FXN) and methylmalonyl-CoA mutase (MCM), both in vitro, in patientsʼ cells and in vivo, in mouse models. TAT-MTS-Mitochondrial fusion proteins are rapidly and efficiently internalizing into cells and their mitochondria, both in patientsʼ cells and into mice tissues, including the brain. Treatment with the new TAT-MTS-Mitochondrial fusion proteins, improves mitochondrial functions and life span in animal models. One such fusion protein TAT-MTS-LAD is now being developed for human use. The novel approach may open new inroads in management of many incurable mitochondrial diseases.
Dr. Lorberboum-Galski is a Full Professor at the Department of Biochemistry and Molecular Biology, Faculty of Medicine, Hebrew University of Jerusalem. After receiving her Ph.D. in Biochemistry from the Hebrew University, she became a postdoctoral fellow at the Laboratory of Molecular Biology, NCI, NIH, USA. Her main research area is Developing reagents for Targeted Human Therapy with the lately focus of mitochondrial genetic diseases. She published over 65 publications in peer-reviewed journals, review articles, edited a book on chimeric proteins and holds several patents. She served as the Head of the Department, Head of the Program for Biochemistry at the Faculty and many other committees. For the last five years she is the Chairman of the Institute for Medical Research (IMRIC) at the Faculty of Medicine, Hebrew University.
Department of Regenerative Medicine and Translational Science, Calcutta School of Tropical Medicine, India
A wound not showing any improvement or healing between 4 to 8 weeks can be classified as a chronic non-healing ulcer. Chronic non-healing ulcer is a major health problem globally. The etiology of non-healing ulcer includes venous, arterial, diabetic, atherosclerotic occlusion, traumatic and pressure ulcers etc.
Diabetes is a major non-traumatic cause of chronic non-healing ulcers affecting mainly the lower limbs. Approximately 15-25% of diabetic patients develop diabetic foot ulcer (DFU) often resulting in amputation. Morbidity is high in many cases as healing is further complicated due to diabetic neuropathy and patients become susceptible to secondary infections due to altered immunity associated with diabetes.
Application of dry, dehydrated or 1 percent glutaraldehide treated amniotic membrane for treating non-healing ulcers has been in practice for some time. The primary aim of the processed amniotic membrane is to act as a biological dressing model by preventing exudation and infection at the wound site and help in re-epithelialisation and suppression of fibrosis.
However, most of these processed amniotic membranes might fail to directly participate in wound healing mechanism as they are devoid of cellular and growth factors, cytokine components which are predominantly lost during the time of chemical or physical processing of the amniotic membrane.
Since 1999, Niranjan Bhattacharya and his associates, showed that application of freshly collected, unprocessed and serologically screened for infection, amniotic membrane, which is rich in inflammatory and non inflammatory cytokines, growth factors and progenitor cells, when applied within 4 hours of collection from lower uterine caesarean section, in patients suffering from traumatic and non-traumatic non-healing ulcers including refractory diabetic ulcers and arteritis induced ulcers, actively participates in wound healing process by formation of granulation tissues and complete re-epithelialisation, due to mesenchymal stem cells from the amniotic membrane.
Dr. Niranjan Bhattacharya holds a MD in Obstetrics and Gynaecology, MS in General Surgery and a DSC in Developmental Immunology. His principal specializations are cell and tissue therapy. Has presented Invited lectures in several international universities and institutions. Has published widely in international and national journals on cord blood and regenerative medicine; is the co-editor of five books on the subject published by Springer. Currently, Chair Professor and Head of the Department, Regenerative Medicine and Translational Science, and Director General, first Public Cord Blood Bank in India, Calcutta School of Tropical Medicine, Kolkata. Cited among top five global cord blood influencers by BioInformant.