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Harnessing H2S to induce hibernation-like state of mesenchymal stromal cells as a strategy for efficient non-freezing cell preservation

Duration of the project: 2025-2026.

Description of the project:

Mesenchymal stromal cells (MStroC) represent one of the most promising tools in regenerative medicine due to their regenerative and immunomodulatory properties. However, their clinical application is limited by significantly reduced survival and functionality after cryopreservation, which highlights the need to improve their storage strategies before transplantation. The main objective of this project is to develop an innovative, non-cryogenic method for MStroC preservation by using a hydrogen sulfide (H₂S) donor to induce a state of low metabolic activity similar to hibernation, thereby protecting cells from cold stress during short-term storage at 4°C, while preserving their viability, regenerative and immunomodulatory potential upon rewarming. Through the collaboration of a Serbian and French team, the project aims to create a new and efficient platform for short-term storage of MStroC at 4°C. This approach would enable better preparation, transport, and clinical application of MStroC as advanced therapeutic products (ATMPs) in regenerative medicine and cell therapies.

Тип пројекта:

Bilateral Scientific Cooperation

Development of mucoadhesive films with amniotic membrane homogenate for the potential application in oral tissue regeneration

Project leader: Dr. Ivana Okić Đorđević

Project collaborators: Dr. Hristina Obradović, Dr. Drenka Trivanović, Dr. Ivana Drvenica, Dr. Sanja Momčilović

Project number: 337-00-110/2023-05/36

Duration of the project: Jul 2023-Jun 2025.

Leading institution: Institute for Medical Research, University of Belgrade

Collaborating institution: Institute of Cell Biology, University of Ljubljana

Description of the project:

Human amniotic membrane (hAM) is an available, inexpensive, and biocompatible collagen-based extracellular matrix with the cells derived from human placenta. hAM and its derivatives possess anti-inflammatory and regenerative properties. Until now, hAM has been used for post-operative and post-traumatic skin defects, intra-oral and genital reconstruction, and ophthalmologic disorders. In recent decades, the regenerative and modulatory properties of stem cells (SCs) have gained the attention of scientists indicating the possibility of their use in cell therapy. Periodontal ligament SCs (PDLSCs), obtained after tooth extraction for orthodontic reasons are recently discovered cells playing a crucial role in oral tissue homeostasis. Since the outcomes of currently available wound healing treatment approaches of oral tissues are expensive and sometimes not predictable, the search for new molecules with regenerative potential is an important goal in oral tissue regeneration. For this purpose, the objectives of this project include the influence of hAM on wound healing and regenerative potential of PDLSCs.

Тип пројекта:

Bilateral Scientific Cooperation

Metabolic effects of bone marrow adipose tissue on multiple myeloma

Project leader: Dr. Drenka Trivanović

Project collaborators: Dr. Ivana Okić Djordjević, Dr. Aleksandra Jauković, Dr. Marijana Kovačić, Dr. Sanja Momčilović, Milena Živanović

Project number:

Duration of the project: 2023-2024.

Leading institution: Julius-Maximilians-Universität Würzburg – Department for Musculoskeletal Tissue Regeneration

Collaborating institution: Institute for Orthopedic Surgery “Banjica”

Description of the project:

Multiple myeloma (MM) is the hematologic malignancy and incurable clonal disease of the plasma cell that grows within the bone marrow (BM) causing destructive bone lesions. As disease of elderly, MM is associated with increased bone marrow adipose tissue (BMAT) that might provide supportive microenvironment for MM cell growth, survival and drug resistance. Since adipocytes were shown to support cancer cell growth by influencing cell mitochondrial activity and lipid metabolism, this project aims to decipher whether BM adipocytes (BMAd) population represents one of the key regulators of MM persistence by controlling fatty acid oxidation (FAO) in MM cells. To address this issue, we will determine the lipid profile of femoral bone marrow, as well as metabolic fitness of plasma and BMAT cells in MM patients. In parallel, lipid and mitochondria exchange at single-cell level will be analyzed in advanced cultures of BMAT and MM cells. Particularly, the role of Kisspeptin-1 receptor signaling in BMAT and MM fatty acid exchange will be explored.

Тип пројекта:

Bilateral Scientific Cooperation

Interaction between the transcription factor p53 and the wnt signaling pathway in the maintenance of stemness in mesenchymal stem cells

Project leader: Dr. Jelena Krstić

Project collaborators: Dr. Drenka Trivanović, Dr. Hristina Obradović, Dr. Tamara Kukolj, Dr. Ivana Okić Đorđević

Project number: 451-03-01039/2015-09/31

Duration of the project: 2016-2017.

Leading institution: Institute for Medical Research, University of Belgrade

Description of the project:

Stem cell self-renewal and differentiation are tightly regulated processes that contribute to the maintenance of tissue homeostasis. The transcription factor p53 is known to regulate these processes in embryonic and adult stem cells in a dual manner through the Wnt signaling pathway. Within this project, the role of p53 and Wnt signaling in the regulation of self-renewal and differentiation of mesenchymal stem cells derived from perinatal tissues, including the umbilical cord and amnion, was investigated. For this purpose, the expression of pluripotency markers (Nanog, Sox2, Oct4) and markers of adipogenic/osteogenic differentiation potential (PPARγ, adiponectin, Runx2, osteocalcin) was analyzed in mesenchymal stem cells from perinatal tissues. Conditions of induced or suppressed p53 expression in these cells were established using gene transfection methods or specific pharmacological activators/inhibitors, including nutlin and pifithrin.

Тип пројекта:

Bilateral Scientific Cooperation

Human culture-expanded adipose stromal/stem cells: serial expansion and maintenance of their proliferative, multipotential and regulatory properties

Project leader: Dr. Aleksandra Jauković

Project collaborators: Dr. Diana Bugarski, Dr. Jelena Kocić, Dr. Drenka Trivanović

Project number: 451-03-02338/2012-14/05

Duration of the project: 2013-2014.

Leading institution: Institute for Medical Research, University of Belgrade

Description of the project:

The use of stem/stromal cells derived from adipose tissue as an autologous source of various differentiated cells has great potential for application in regenerative medicine. This project aimed to define effective methods of multipotent stem/stromal cell extraction from adipose tissue (ASC), their expansion and differentiation ex vivo, as well as the examination of their survival and proliferation upon cryopreservation. In addition, the characteristics of ASCs propagated ex vivo were compared in different cell culture model systems, including cultivation in bioreactors and 3D tissue cultures on biomaterial scaffolds. Also, the important aim of this project included investigations of ASCs effects on the proliferation of various tumor cell lines with special emphasis on the maintenance of ASCs biological characteristics and immunoregulatory properties during long-term culture expansion procedures in order to confirm the safety of their clinical use.

Тип пројекта:

Bilateral Scientific Cooperation

Role of IL-6/NF-κB/HIF-1 axis in adipose tissue mesenchymal stromal cells-mediated breast cancer cells stemness

Project leader: Dr. Drenka Trivanović

Project collaborators: Dr. Aleksandra Jauković, Dr. Ivana Okić Đorđević, Dr. Tamara Kukolj

Project number: SK-SRB-2016-0031

Duration of the project: 2017-2018.

Leading institution: Institute for Medical Research, University of Belgrade

Description of the project:

Mesenchymal stromal/ stem cells (MSC) from adipose tissue play an important role in the tumor microenvironment of breast cancer, but the molecular basis of their participation in the regulation of tumor development and progression is insufficiently studied. Persistent inflammation and hypoxia in tumor tissue contribute to the development of cancer stem cells and tumor progression, where transcription factors NF-κB and HIF-1 cooperate to govern the cancer progression.

In order to define potential new targets for the development of antitumor therapeutic strategies, this project aimed to define molecular mechanisms underlying the influence of adipose tissue MSC on stemness properties of breast tumor cells with a special focus on the participation of IL-6/NF-κB/HIF-1 signaling pathway. For these purposes, the effects of MSC adipose tissue or their produced factors on breast tumor cell line MDA-MB-231 were analyzed in terms of mammospheres formation, expression of pluripotency markers, cell cycle/silencing, and modification of NF-κB and/or HIF-1 activation.

Тип пројекта:

Bilateral Scientific Cooperation