Cell replacement therapy with stem cells in multiple sclerosis, a systematic review

Human Cell https://doi.org/10.1007/s13577-023-01006-1 REVIEW ARTICLE Cell replacement therapy with stem cells in multiple sclerosis, a systematic review Maria Veatriki Christodoulou1 · Ermioni Petkou1 · Natalia Atzemoglou1 · Eleni Gkorla1 · Aikaterini Karamitrou1 · Yannis V. Simos1 · Stefanos Bellos1 · Chryssa Bekiari2 · Panos Kouklis3 · Spyridon Konitsiotis4 · Patra Vezyraki1 · Dimitrios Peschos1 · Konstantinos I. Tsamis1,4 Received: 2 August 2023 / Accepted: 26 October 2023 © The Author(s) 2023 Abstract Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS), characterized by demyelination and axonal loss. It is induced by attack of autoreactive lymphocytes on the myelin sheath and endogenous remyelination failure, eventually leading to accumulation of neurological disability. Disease-modifying agents can successfully address inflammatory relapses, but have low efficacy in progressive forms of MS, and cannot stop the progressive neurodegenerative process. Thus, the stem cell replacement therapy approach, which aims to overcome CNS cell loss and remyelination failure, is considered a promising alternative treatment. Although the mechanisms behind the beneficial effects of stem cell transplantation are not yet fully understood, neurotrophic support, immunomodulation, and cell replacement appear to play an important role, leading to a multifaceted fight against the pathology of the disease. The present systematic review is focusing on the efficacy of stem cells to migrate at the lesion sites of the CNS and develop functional oligodendrocytes remyelinating axons. While most studies confirm the improvement of neurological deficits after the administration of different stem cell types, many critical issues need to be clarified before they can be efficiently introduced into clinical practice. Keywords Demyelination · Remyelination · Multiple sclerosis · Neural stem cells · Oligodendrocytes · Stem cell · Transplantation Introduction Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) primarily associated with demyelination of the neural axons but also leading to axonal degradation and neurodegeneration. As a consequence, neuronal impulses are not adequately * Konstantinos I. Tsamis 1 Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece 2 Laboratory of Anatomy and Histology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece 3 Laboratory of Biology, Department of Medicine, University of Ioannina, Ioannina, Greece 4 Department of Neurology, University Hospital of Ioannina, Ioannina, Greece transmitted and patients develop neurological symptoms. It is one of the main causes of disability in young adults and its incidence is increasing [1]. The pathogenesis of the disease is complex and has not yet been fully unraveled [2]. It is considered that the onset of the disease long precedes the first clinical symptoms. Existing immunomodulatory agents, despite being very efficient in reducing the rate of relapses, do not prevent progressive neurodegenerative processes, nor do they have any regenerative effect, while they may cause significant adverse effects [3]. A stem cell is an undifferentiated cell that can self-renew and differentiate into tissue-specific cell types. During the lifetime of an organism stem cells are able to act as repair cells, regenerating cells of organs. The behavior and properties of stem cells are regulated by their immediate environment, the niche [4]. Depending on their properties, stem cells can be divided into three main categories: pluripotent stem cells, totipotent stem cells, and multipotent stem cells. Pluripotent stem cells can differentiate into all tissue types 13 Vol.:(0123456789) M. V. Christodoulou et al. except extra-embryonic tissues [5]. This category includes embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs are derived from the cells of the inner mass of the blastocyst during early embryogenesis and their differentiation in vitro is an important chapter in regenerative medicine [6]. iPSCs are generated in vitro from a patient’s own fully differentiated somatic cells by the process of cellular reprogramming [5], [7]. Totipotent stem cells include zygotes and blastomeres up to the eight-cell stage and have the ability to differentiate into all cell types needed to create a complete organism [8]. Finally, multipotent stem cells include stem cells of embryonic (fetal stem cells, FSCs) and adult tissues (adult stem cells, ASCs), and can differentiate into limited cell types of the tissue or the organ where they are found [5]. FSCs are mesenchymal-type cells that originate in the tissues of the fetus, can be found in the circulation during the first trimester of pregnancy and differentiate into bone, cartilage, haematopoietic cells, and oligodendrocytes [9]. ASCs are located in the niche of all body tissues, and their main function is to produce specialized cells for repair in case of damage, injury or disease. They include mesenchymal stromal cells (MSCs), hematopoietic stem cells (HSCs), stem cells from muscle tissue, and neural stem cells (NSCs) [10]. Due to their ability to self-renew and differentiate, stem cells have recently been proposed as a promising treatment for various degenerative and autoimmune disorders, including MS [11], [12]. The underlying mechanisms for the beneficial effects of administered stem cells include immunomodulation, transforming the central nervous system microenvironment from hostile to supportive and neurotrophic action, promoting the differentiation and regeneration of endogenous oligodendrocytes [13]. Despite all, their most interesting function is cell replacement, meaning their use as an exogenous source for the production of new oligodendrocytes that could possibly restore the damaged myelin sheaths. This review aims to present and clarify the role of stem cell replacement therapy in MS, to reveal the types of stem cells that perform cell replacement and their optimal route of administration. reference lists of published articles were searched manually, to ensure the comprehensiveness of the bibliography. This effort resulted in 263 citations, from which relevant studies were selected for the review. Their potential relevance was examined and 129 studies were excluded as irrelevant. The full texts of the remaining 134 citations were assessed to select those primary studies that directly related to stem cell replacement therapy in multiple sclerosis. These criteria excluded 54 studies and left 80 in the review. Hematopoietic stem cells (HSCs) HSCs constitute approximately 0.01% of the proliferating cells in the bone marrow and they can generate all hematopoietic cell lines, including erythrocytes, megakaryocyte (...truncated)