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Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus

Lee SH, Khoo AS, Griffiths JR, Mat Lazim N

Int J Cancer, 2025 Feb 01;156(3):488-498.
PMID: 39291683 DOI: 10.1002/ijc.35192

The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.

Matched MeSH terms: Stromal Cells/metabolism; Stromal Cells/pathology; Stromal Cells/virology
Role of circular RNAs in determining the fate of mesenchymal stem cells

Wong RSY, Cheong SK

Malays J Pathol, 2021 Aug;43(2):241-250.
PMID: 34448788

Ribonucleic acid (RNA) has been well-understood for its linear form for many years. With advances in high-throughput sequencing, there is an increasing focus on circular RNAs (circRNAs) recently. Although they were previously regarded as splicing error by-products, research has shown that they play a pivotal role in many cellular processes, one of which is the control of stem cell differentiation and fate. On the other hand, decades of research have demonstrated the promising therapeutic potential of mesenchymal stem cells (MSCs). To this end, there is a growing body of research on the role of circRNAs in the determination of the fate of MSCs. This review critically examines the current evidence and consolidates key findings from studies that explore the involvement of circRNAs in the regulation of MSC differentiation.

Matched MeSH terms: Mesenchymal Stromal Cells*
Fulltext Mesenchymal stem cells: angels or demons?

Wong RS

J Biomed Biotechnol, 2011;2011:459510.
PMID: 21822372 DOI: 10.1155/2011/459510

Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment.

Matched MeSH terms: Mesenchymal Stromal Cells*
Menstrual blood-derived endometrial stem cell, a unique and promising alternative in the stem cell-based therapy for chemotherapy-induced premature ovarian insufficiency

Zhang S, Yahaya BH, Pan Y, Liu Y, Lin J

Stem Cell Res Ther, 2023 Nov 13;14(1):327.
PMID: 37957675 DOI: 10.1186/s13287-023-03551-w

Chemotherapy can cause ovarian dysfunction and infertility since the ovary is extremely sensitive to chemotherapeutic drugs. Apart from the indispensable role of the ovary in the overall hormonal milieu, ovarian dysfunction also affects many other organ systems and functions including sexuality, bones, the cardiovascular system, and neurocognitive function. Although conventional hormone replacement therapy can partly relieve the adverse symptoms of premature ovarian insufficiency (POI), the treatment cannot fundamentally prevent deterioration of POI. Therefore, effective treatments to improve chemotherapy-induced POI are urgently needed, especially for patients desiring fertility preservation. Recently, mesenchymal stem cell (MSC)-based therapies have resulted in promising improvements in chemotherapy-induced ovary dysfunction by enhancing the anti-apoptotic capacity of ovarian cells, preventing ovarian follicular atresia, promoting angiogenesis and improving injured ovarian structure and the pregnancy rate. These improvements are mainly attributed to MSC-derived biological factors, functional RNAs, and even mitochondria, which are directly secreted or indirectly translocated with extracellular vesicles (microvesicles and exosomes) to repair ovarian dysfunction. Additionally, as a novel source of MSCs, menstrual blood-derived endometrial stem cells (MenSCs) have exhibited promising therapeutic effects in various diseases due to their comprehensive advantages, such as periodic and non-invasive sample collection, abundant sources, regular donation and autologous transplantation. Therefore, this review summarizes the efficacy of MSCs transplantation in improving chemotherapy-induced POI and analyzes the underlying mechanism, and further discusses the benefit and existing challenges in promoting the clinical application of MenSCs in chemotherapy-induced POI.

Matched MeSH terms: Mesenchymal Stromal Cells*
Fulltext Empowering Mesenchymal Stem Cells for Ocular Degenerative Disorders

Ding SSL, Subbiah SK, Khan MSA, Farhana A, Mok PL

Int J Mol Sci, 2019 Apr 10;20(7).
PMID: 30974904 DOI: 10.3390/ijms20071784

Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite the known therapeutic role and mechanisms of MSCs, low cell precision towards the targeted area and cell survivability at tissue needing repair often resulted in a disparity in therapeutic outcomes. In this review, we will discuss the current and feasible strategy options to enhance treatment outcomes with MSC therapy. We will review the application of various types of biomaterials and advances in nanotechnology, which have been employed on MSCs to augment cellular function and differentiation for improving treatment of visual functions. In addition, several modes of gene delivery into MSCs and the types of associated therapeutic genes that are important for modulation of ocular tissue function and repair will be highlighted.

Matched MeSH terms: Mesenchymal Stromal Cells/metabolism*; Mesenchymal Stromal Cells/pathology
Mesenchymal stromal cell-like characteristics of corneal keratocytes

Choong PF, Mok PL, Cheong SK, Then KY

Cytotherapy, 2007;9(3):252-8.
PMID: 17464757

The unique potential of mesenchymal stromal cells (MSC) has generated much research interest recently, particularly in exploring the regenerative nature of these cells. Previously, MSC were thought to be found only in the BM. However, further studies have shown that MSC can also be isolated from umbilical cord blood, adipose tissue and amniotic fluid. In this study, we explored the possibility of MSC residing in the cornea.

Matched MeSH terms: Stromal Cells*; Mesenchymal Stromal Cells*
Fulltext Mesenchymal stromal cells for cartilage repair in osteoarthritis

Mamidi MK, Das AK, Zakaria Z, Bhonde R

Osteoarthritis Cartilage, 2016 Aug;24(8):1307-16.
PMID: 26973328 DOI: 10.1016/j.joca.2016.03.003

Treatment for articular cartilage damage is quite challenging as it shows limited repair and regeneration following injury. Non-operative and classical surgical techniques are inefficient in restoring normal anatomy and function of cartilage in osteoarthritis (OA). Thus, investigating new and effective strategies for OA are necessary to establish feasible therapeutic solutions. The emergence of the new discipline of regenerative medicine, having cell-based therapy as its primary focus, may enable us to achieve repair and restore the damaged articular cartilage. This review describes progress and development of employing mesenchymal stromal cell (MSC)-based therapy as a promising alternative for OA treatment. The objective of this review is to first, discuss how in vitro MSC chondrogenic differentiation mimics in vivo embryonic cartilage development, secondly, to describe various chondrogenic differentiation strategies followed by pre-clinical and clinical studies demonstrating their feasibility and efficacy. However, several challenges need to be tackled before this research can be translated to the clinics. In particular, better understanding of the post-transplanted cell behaviour and learning to enhance their potency in the disease microenvironment is essential. Final objective is to underscore the importance of isolation, storage, cell shipment, route of administration, optimum dosage and control batch to batch variations to realise the full potential of MSCs in OA clinical trials.

Matched MeSH terms: Mesenchymal Stromal Cells*
Response to: 'Umbilical-cord messenchymal stem cells for the treatment of automimmune diseases: beware of cell to cell contact' by Alunno et al

Lim TO, Deng D, Zhang P, Guo Y

Ann Rheum Dis, 2018 03;77(3):e15.
PMID: 28663307 DOI: 10.1136/annrheumdis-2017-211808
Matched MeSH terms: Mesenchymal Stromal Cells*
Senotherapeutics for mesenchymal stem cell senescence and rejuvenation

Wong PF, Dharmani M, Ramasamy TS

Drug Discov Today, 2023 Jan;28(1):103424.
PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424

Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.

Matched MeSH terms: Mesenchymal Stromal Cells*
Mesenchymal Stromal Cells-Derived Exosome and the Roles in the Treatment of Traumatic Brain Injury

Mot YY, Moses EJ, Mohd Yusoff N, Ling KH, Yong YK, Tan JJ

Cell Mol Neurobiol, 2023 Mar;43(2):469-489.
PMID: 35103872 DOI: 10.1007/s10571-022-01201-y

Traumatic brain injury (TBI) could result in life-long disabilities and death. Though the mechanical insult causes primary injury, the secondary injury due to dysregulated responses following neuronal apoptosis and inflammation is often the cause for more detrimental consequences. Mesenchymal stromal cell (MSC) has been extensively investigated as the emerging therapeutic for TBI, and the functional properties are chiefly attributed to their secretome, especially the exosomes. Delivering these nanosize exosomes have shown to ameliorate post-traumatic injury and restore brain functions. Recent technology advances also allow engineering MSC-derived exosomes to carry specific biomolecules of interest to augment their therapeutic outcome. In this review, we discuss the pathophysiology of TBI and summarize the recent progress in the applications of MSCs-derived exosomes, the roles and the signalling mechanisms underlying the protective effects in the treatment of the TBI.

Matched MeSH terms: Mesenchymal Stromal Cells*
Bone marrow-derived mesenchymal stem cells: A promising therapeutic option for the treatment of diabetic foot ulcers

Dama G, Du J, Zhu X, Liu Y, Lin J

Diabetes Res Clin Pract, 2023 Jan;195:110201.
PMID: 36493913 DOI: 10.1016/j.diabres.2022.110201

Chronic wounds fail to heal through the three normal stages of healing (inflammatory, proliferative, and remodelling), resulting in a chronic tissue injury that is not repaired within the average time limit. Patients suffering from type 1 and type 2 diabetes are prone to develop diabetic foot ulcers (DFUs), which commonly develop into chronic wounds that are non treatable with conventional therapies. DFU develops due to various risk factors, such as peripheral neuropathy, peripheral vascular disease, arterial insufficiency, foot deformities, trauma and impaired resistance to infection. DFUs have gradually become a major problem in the health care system worldwide. In this review, we not only focus on the pathogenesis of DFU but also comprehensively summarize the outcomes of preclinical and clinical studies thus far and the potential therapeutic mechanism of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of DFU. Based on the published results, BMSC transplantation can contribute to wound healing through growth factor secretion, anti-inflammation, differentiation into tissue-specific cells, neovascularization, re-epithelialization and angiogenesis in DFUs. Moreover, clinical trials showed that BMSC treatment in patients with diabetic ulcers improved ulcer healing and the ankle-brachial index, ameliorated pain scores, and enhanced claudication walking distances with no reported complications. In conclusion, although BMSC transplantation exhibits promising therapeutic potential in DFU treatment, additional studies should be performed to confirm their efficacy and long-term safety in DFU patients.

Matched MeSH terms: Mesenchymal Stromal Cells*
Mesenchymal stem cells in the management of oral submucous fibrosis-An enigma to be solved

Kizhakkoottu S, Ramani P, Tilakaratne WM

J Oral Pathol Med, 2024 May;53(5):275-276.
PMID: 38685571 DOI: 10.1111/jop.13539
Matched MeSH terms: Mesenchymal Stromal Cells*
Reversal of Neuropsychiatric Comorbidities in an Animal Model of Temporal Lobe Epilepsy Following Systemic Administration of Dental Pulp Stem Cells and Bone Marrow Mesenchymal Stem Cells

Senthilkumar S, Maiya K, Jain NK, Mata S, Mangaonkar S, Prabhu P, et al.

Curr Gene Ther, 2023;23(3):198-214.
PMID: 36305152 DOI: 10.2174/1566523223666221027113723

INTRODUCTION: We aim to investigate whether timed systemic administration of dental pulp stem cells (DPSCs) or bone marrow mesenchymal stem cells (BM-MSCs) with status epilepticus (SE) induced blood-brain barrier (BBB) damage could facilitate the CNS homing of DPSCs/BM-MSCs and mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of Temporal Lobe epilepsy (TLE).
BACKGROUND: Cognitive impairments, altered emotional responsiveness, depression, and anxiety are the common neuropsychiatric co-morbidities observed in TLE patients. Mesenchymal stem cells (MSCs) transplantation has gained immense attention in treating TLE, as ~30% of patients do not respond to anti-epileptic drugs. While MSCs are known to cross the BBB, better CNS homing and therapeutic effects could be achieved when the systemic administration of MSC is timed with BBB damage following SE.
OBJECTIVES: The objectives of the present study are to investigate the effects of systemic administration of DPSCs/BM-MSCs timed with BBB damage on CNS homing of DPSCs/BM-MSCs, neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of TLE.
METHODOLOGY: We first assessed the BBB leakage following kainic acid-induced SE and timed the intravenous administration of DPSCs/BM-MSCs to understand the CNS homing/engraftment potential of DPSCs/BM-MSCs and their potential to mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities.
RESULTS: Our results revealed that systemic administration of DPSCs/BM-MSCs attenuated neurodegeneration, neuroinflammation, and ameliorated neuropsychiatric comorbidities. Three months following intravenous administration of DPSCs/BM-MSCs, we observed a negligible number of engrafted cells in the corpus callosum, sub-granular zone, and sub-ventricular zone.
CONCLUSION: Thus, it is evident that functional recovery is still achievable despite poor engraftment of MSCs into CNS following systemic administration.

Matched MeSH terms: Mesenchymal Stromal Cells*
Fulltext Hope on the horizon: Wharton's jelly mesenchymal stem cells in the fight against COVID-19

Gupta G, Hussain MS, Thapa R, Dahiya R, Mahapatra DK, Bhat AA, et al.

Regen Med, 2023 Sep;18(9):675-678.
PMID: 37554111 DOI: 10.2217/rme-2023-0077
Matched MeSH terms: Mesenchymal Stromal Cells*
Fulltext The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration

Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R

Cytotherapy, 2016 Jan;18(1):13-24.
PMID: 26631828 DOI: 10.1016/j.jcyt.2015.10.008

The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications.

Matched MeSH terms: Mesenchymal Stromal Cells/cytology; Mesenchymal Stromal Cells/secretion*
Fulltext Mesenchymal stem cells inhibit proliferation of lymphoid origin haematopoietic tumour cells by inducing cell cycle arrest

Sarmadi VH, Tong CK, Vidyadaran S, Abdullah M, Seow HF, Ramasamy R

Med J Malaysia, 2010 Sep;65(3):209-14.
PMID: 21939170

We have previously shown that mesenchymal stem cells (MSC) inhibit tumour cell proliferation, thus promising a novel therapy for treating cancers. In this study, MSC were generated from human bone marrow samples and characterised based on standard immunophenotyping. When MSC were co-cultured with BV173 and Jurkat tumour cells, the proliferation of tumour cells were profoundly inhibited in a dose dependent manner mainly via cell to cell contact interaction. Further cell cycle analysis reveals that MSC arrest tumour cell proliferation in G0/G1 phase of cell cycle thus preventing the entry of tumour cells into S phase of cell cycle.

Matched MeSH terms: Mesenchymal Stromal Cells/metabolism; Mesenchymal Stromal Cells/physiology*
Fulltext Cellular mechanisms of emerging applications of mesenchymal stem cells

Mok PL, Leong CF, Cheong SK

Malays J Pathol, 2013 Jun;35(1):17-32.
PMID: 23817392 MyJurnal

Mesenchymal stem cells (MSC) are multipotent, self-renewing cells that can be found mainly in the bone marrow, and other post-natal organs and tissues. The ease of isolation and expansion, together with the immunomodulatory properties and their capability to migrate to sites of inflammation and tumours make them a suitable candidate for therapeutic use in the clinical settings. We review here the cellular mechanisms underlying the emerging applications of MSC in various fields.

Matched MeSH terms: Mesenchymal Stromal Cells/physiology*
Fulltext Potential of Exosomes as Cell-Free Therapy in Articular Cartilage Regeneration: A Review

Ng CY, Chai JY, Foo JB, Mohamad Yahaya NH, Yang Y, Ng MH, et al.

Int J Nanomedicine, 2021;16:6749-6781.
PMID: 34621125 DOI: 10.2147/IJN.S327059

Treatment of cartilage defects such as osteoarthritis (OA) and osteochondral defect (OCD) remains a huge clinical challenge in orthopedics. OA is one of the most common chronic health conditions and is mainly characterized by the degeneration of articular cartilage, shown in the limited capacity for intrinsic repair. OCD refers to the focal defects affecting cartilage and the underlying bone. The current OA and OCD management modalities focus on symptom control and on improving joint functionality and the patient's quality of life. Cell-based therapy has been evaluated for managing OA and OCD, and its chondroprotective efficacy is recognized mainly through paracrine action. Hence, there is growing interest in exploiting extracellular vesicles to induce cartilage regeneration. In this review, we explore the in vivo evidence of exosomes on cartilage regeneration. A total of 29 in vivo studies from the PubMed and Scopus databases were identified and analyzed. The studies reported promising results in terms of in vivo exosome delivery and uptake; improved cartilage morphological, histological, and biochemical outcomes; enhanced subchondral bone regeneration; and improved pain behavior following exosome treatment. In addition, exosome therapy is safe, as the included studies documented no significant complications. Modifying exosomal cargos further increased the cartilage and subchondral bone regeneration capacity of exosomes. We conclude that exosome administration is a potent cell-free therapy for alleviating OA and OCD. However, additional studies are needed to confirm the therapeutic potential of exosomes and to identify the standard protocol for exosome-based therapy in OA and OCD management.

Matched MeSH terms: Mesenchymal Stromal Cells*
Therapeutic potential of human umbilical cord-derived mesenchymal stem cells transplantation in rats with optic nerve injury

Looi SY, Bastion MC, Leow SN, Luu CD, Hairul NMH, Ruhaslizan R, et al.

Indian J Ophthalmol, 2022 Jan;70(1):201-209.
PMID: 34937239 DOI: 10.4103/ijo.IJO_473_21

Purpose: There are no effective treatments currently available for optic nerve transection injuries. Stem cell therapy represents a feasible future treatment option. This study investigated the therapeutic potential of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in rats with optic nerve injury.
Methods: Sprague-Dawley (SD) rats were divided into three groups: a no-treatment control group (n = 6), balanced salt solution (BSS) treatment group (n = 6), and hUC-MSCs treatment group (n = 6). Visual functions were assessed by flash visual evoked potential (fVEP) at baseline, Week 3, and Week 6 after optic nerve crush injury. Right eyes were enucleated after 6 weeks for histology.
Results: The fVEP showed shortened latency delay and increased amplitude in the hUC-MSCs treated group compared with control and BSS groups. Higher cellular density was detected in the hUC-MSC treated group compared with the BSS and control groups. Co-localized expression of STEM 121 and anti-S100B antibody was observed in areas of higher nuclear density, both in the central and peripheral regions.
Conclusion: Peribulbar transplantation of hUC-MSCs demonstrated cellular integration that can potentially preserve the optic nerve function with a significant shorter latency delay in fVEP and higher nuclear density on histology, and immunohistochemical studies observed cell migration particularly to the peripheral regions of the optic nerve.

Matched MeSH terms: Mesenchymal Stromal Cells*
Fulltext Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?

Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, et al.

Cell Death Dis, 2022 Jul 04;13(7):580.
PMID: 35787632 DOI: 10.1038/s41419-022-05034-x

Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.

Matched MeSH terms: Mesenchymal Stromal Cells*

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