Current Stem Cell Research & Therapy - Volume 17, Issue 4, 2022

Mesenchymal stem cells derived from postnatal orofacial tissues can be readily isolated and possess diverse origins, for example, from surgically removed teeth or gingiva. These cells exhibit stem cell properties, strong potential for self-renewal, and show multi-lineage differentiation, and they have therefore been widely employed in stem cell therapy, tissue regeneration, and inflammatory diseases. Among them, stem cells from human exfoliated deciduous teeth [SHED] and their derivatives have manifested wide application in the treatment of diseases because of their outstanding advantages— including convenient access, easy storage, and less immune rejection. Numerous studies have shown that most diseases are closely associated with inflammation and that inflammatory diseases are extremely destructive, can lead to necrosis of organ parenchymal cells, and can deposit excessive extracellular matrix in the tissues. Inflammatory diseases are thus the principal causes of disability and death from many diseases worldwide. SHED and their derivatives not only exhibit the basic characteristics of stem cells but also exhibit some special properties of their own, particularly with regard to their great potential in inhibiting inflammation and tissue regeneration. SHED therapy may provide a new direction for the treatment of inflammation and corresponding tissue defects. In this review, we critically analyze and summarize the latest findings on the behaviors and functions of SHED, serumfree conditioned medium from SHED [SHED-CM], and extracellular vesicles, especially exosomes, from SHED [SHED-Exos], and discuss their roles and underlying mechanisms in the control of inflammatory diseases, thus further highlighting additional functions for SHED and their derivatives in future therapies.

Background: Benefiting from in-depth research into stem cells, extracellular vesicles (EVs), which are byproducts of cells and membrane-wrapped microvesicles (30-120 nm) containing lipids, proteins, and nucleic acids, may cast light on the research and development of therapeutics capable of improving the neurological recovery of spinal cord injury (SCI) animals. However, the mechanistic modes of action for EVs in alleviating the lesion size of SCI remain to be solved, thus presenting a tremendous gap existing in translation from the laboratory to the clinic. Objective: The purpose of this minireview was to cover a wide range of basic views on EVs involved in SCI treatment, including the effects of EVs on the pathogenesis, treatment, and diagnosis of spinal cord injury. Methods: We searched databases (i.e., PubMed, Web of Science, Scopus, Medline, and EMBASE) and acquired all accessible articles published in the English language within five years. Studies reporting laboratory applications of EVs in the treatment of SCI were included and screened to include studies presenting relevant molecular mechanisms. Results: This review first summarized the basic role of EVs in cell communication, cell death, inflammatory cascades, scar formation, neuronal regrowth, and angiogenesis after SCI, thereby providing insights into neuroprotection and consolidated theories for future clinical application of EVs. Conclusion: EVs participate in an extremely wide range of cell activities, play a critical role in cell communication centring neurons, and are considered potential therapies and biomarkers for SCI. miRNAs are the most abundant nucleic acids shipped by EVs and effluent cytokines, and they may represent important messengers of EVs and important factors in SCI treatment.

Mesenchymal stem cells (MSCs) are the most promising candidates for cellular therapies, and most therapeutic applications have focused on MSCs produced from adult bone marrow, despite mounting evidence that MSCs are present in a wide range of conditions. Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells, but its therapeutic potential extends beyond the hematopoietic component, which also suggests solid organ regenerative potential. With potential ranging from embryonic- like to lineage-committed progenitor cells, many different stems and progenitor cell populations have been postulated. MSC is currently inferred by numerous clinical applications for human UCB. As stem cell therapy kicks off some new research and these cells show such a boon to stem cell therapy, it is nevertheless characteristic that the prospect of UCB conservation is gaining momentum. Taken together, the experience described here shows that MSCs derived from UCB are seen as attractive therapeutic candidates for various human disorders including cancer. It is argued that a therapeutic stem cell transplant, using stem cells from UCB, provides a reliable repository of early precursor cells that can be useful in a large number of different conditions, considering issues of safety, availability, transplant methodology, rejection, and side effects. In particular, we focus on the concept of isolation and expansion, comparing the phenotype with MSC derived from the UCB, describing the ability to differentiate, and lastly, the therapeutic potential concerning stromal support, stemness characteristic, immune modulation, and cancer stem cell therapy. Thus it is an overview of the therapeutic application of UCB derived MSCs, with a special emphasis on cancer. Besides, the current evidence on the double-edged sword of MSCs in cancer treatment and the latest advances in UCB-derived MSC in cancer research will be discussed.

Sickle cell disease (SCD) is one of the most common haemoglobinopathies worldwide, with up to 70 % of global SCD annual births occurring in sub-Saharan Africa. Reports have shown that 50 to 80 % of affected children in these countries die annually. Efforts geared towards understanding and controlling HbF production in SCD patients could lead to strategies for effective control of globin gene expression and therapeutic approaches that could be beneficial to individuals with haemoglobinopathies. Hemopoietic stem cells (HSCs) are characterized by a specific miRNA signature in every state of differentiation. The role of miRNAs has become evident both in the maintenance of the “stemness” and in the early induction of differentiation by modulation of the expression of the master pluripotency genes and during early organogenesis. miRNAs are extra regulatory mechanisms in hematopoietic stem cells (HSCs) via influencing transcription profiles together with transcript stability. miRNAs have been reported to be used to reprogram primary somatic cells toward pluripotency. Their involvement in cell editing holds the potential for therapy for many genetic diseases. This review provides a snapshot of miRNA involvement in cell fate decisions, haemoglobin induction pathway, and their journey as some emerge prime targets for therapy in beta haemoglobinopathies.

Background: Neutrophils are involved in the injury of myocytes during myocardial ischemia (MI). Stem cells migrate to the site of myocardial injury under homing signals and play a protective role, such as inhibiting inflammation. Chemokine SDF-1α and its related receptor CXCR4 are upregulated after myocardial infarction, which may play an important role in stem cell homing. Objectives: This study aimed to explore the potential therapeutic effect of SDF-1α-modified bone marrow mesenchymal stem cells on myocardial ischemia/reperfusion (I/R) injury. Methods: We explored the role of SDF-1α modified bone marrow mesenchymal stem cells in vivo and in vitro. SDF-1α and CXCR4 expression was detected under hypoxia/reoxygenation (H/R) condition. Cell migration was detected by the transwell method. The levels of SDF-1α and IL-1β, IL-6, IL-10, and TNF-α were detected in different groups. Results: In vitro, SDF-1α was mainly upregulated and secreted by cardiomyocytes, and cardiomyocytes recruited stem cells through the SDF-1/CXCR4 pathway to reduce the damage of polymorphic mononuclear neutrophils to cardiomyocytes under H/R. Upregulation of SDF-1α increased the migration ability of BMSC Stem Cells to H/R-induced cardiomyocytes. In vivo, intravenous injection of SDF-1α genemodified BMSC Stem Cells reduced inflammatory infiltration in the injured area as well as the level of systemic inflammatory factors. Conclusion: SDF-1α-overexpressing BMSC Stem Cells protected the heart function of mice and significantly reduced I/R-induced myocardial injury, which has a potential protective effect on MI.

Background: The transplantation of bone marrow mesenchymal cells (BMSCs) has been shown to be an effective mean for treating sepsis-related organ damage. Pytoptotic cell death, in turn, has recently been identified as a key driver of sepsis-related damage. At present, there are few studies on the effect of BMSC transplantation on pyroptotic cell death. Objective: We explored the ability of BMSCs to attenuate hepatic damage in a pyroptosis-related manner in a rat model of lipopolysaccharide (LPS)-induced liver injury. Methods: Following injury modeling and BMSC transplantation, we assessed the expression of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, and key downstream pyroptosis-related signaling molecules. Results: It was found that BMSC transplantation was sufficient to significantly improve rat survival after LPS injection. A significantly reduced expression of the pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18 in rats that had undergone BMSC transplantation compared to control animals was observed. Notably, this activity was superior to single-agent administration of the NLRP3 inhibitor MCC950. Conclusion: Our data suggest that BMSC transplantation may alleviate LPS-induced hepatic damage by suppressing the activation of the NLRP3 inflammasome and the induction of pyroptotic cell death.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by progressive cognitive deterioration. All recent therapeutic strategies tend to inhibit the generation of the Aβ peptide. These approaches tend to mediate both α - and γ -secretases to undergo the nonamyloidogenic pathway. ADAM10 is the main α-secretase that cleaves APP, and it is regulated by the metabolic product of vitamin A (retinoic acid), which is being widely used recently in AD research as a target for treatment. Mesenchymal stem cells (MSCs) are also used recently as a promising regenerative therapy for AD. Objectives: The present study aimed to: (1) study the effect of MSCs with/without acitretin on the regulation of Adam10 gene expression in AlCl3-induced AD rat model, and (2) validate the hypothesis that AD is a time-dependent progressive disease that spreads spontaneously even after the stopping of exposure to AlCl3. Methods: The experimental work has been designed to include three successive phases; AlCl3 induction phase (I), AlCl3 withdrawal phase (W), and therapeutic phase (T). Forty-five male albino Wistar rats were randomly divided into 2 main groups: the control (C) group (15 rats) and AD group (30 rats). The therapeutic potential of MSCs with/without acitretin has been evaluated at behavioral, physiological, molecular, and histopathological levels. Results: Among the three therapeutic groups, combined administration of both MSC and acitretin showed the best compensatory effects on most of the measured parameters. Conclusion: The present study approved that AD is a time-dependent progressive disease which spreads spontaneously without more AlCl3 exposure.

Background: Severe peripheral nerve injury, especially the long-distance peripheral nerve defect, causes severe functional disability in patients. There is always a lack of effective repair methods for clinic, and those in practice are associated with side effects. A case study was performed to observe the regenerative outcomes of the surgical repair of long-distance peripheral nerve defects in the upper arm with chitosan-poly(glycolide-co-lactide) (PGLA) nerve grafts combined with bone marrow mononuclear cells (BMMCs). Methods: The right upper arm of a 29-year-old woman was injured, leaving a 50-mm-long median nerve defect, an 80-mm-long ulnar nerve defect, and muscle and blood vessel disruptions. The nerve defects were repaired by implanting BMMC-containing chitosan-PGLA nerve grafts on the 40th day after injury. A series of functional assessments were carried out from 2 weeks to 66 months after surgical repair. Sensory function was assessed by the pinprick test, two-point discrimination test and Semmes-Weinstein monofilament test. Motor function was evaluated by the range of motion of the wrist joint and muscle power. Autonomic function was monitored by laser-Doppler perfusion imaging (LDPI). Tissue morphology was observed through ultrasonic investigations. Results: No adverse events, such as infection, allergy, or rejection, caused by the treatment were detected during the follow-up period. Sensory and pinprick nociception in the affected thumb, index, and middle fingers gradually restored at 6th month after surgery. The monofilament tactile sensation was 0.4 g in the terminal finger pulp of the thumb and index finger, 2.0 g in the middle finger, and greater than 300 g in the ring finger and little finger at the 66th month. Motor function recovery was detected at the 5th month after surgery, when the muscle strength of the affected forearm flexors began to recover. At the 66th month after surgery, the patient's forearm flexor strength was grade 4, with 80° of palmar flexion, 85° of dorsal extension, 8° of radial deviation, 40° of ulnar deviation, 40° of anterior rotation, and 85° of posterior rotation of the affected wrist. The patient could perform holding, picking up, and some other daily activities with the affected hand. The patient's sweating function of the affected hand was close to the level of the healthy hand. LDPI showed that the skin blood flow perfusion was significantly increased, with perfusion similar to on the normal side in some areas. Neuromusculoskeletal ultrasonography showed the presence of nerve structures. Conclusion: These results suggest that chitosan-PGLA nerve grafts combined with BMMCs could effectively repair long-distance nerve defects and achieve good clinical results.