Dental Mesenchymal Stem Cell Secretome: An Intriguing Approach for Neuroprotection and Neuroregeneration

Mesenchymal stem cells (MSCs) are known for their beneficial effects and regenerative potential. In particular, dental-derived MSCs have the advantage of easier accessibility and a non-invasive isolation method. Moreover, thanks to their neural crest origin, dental MSCs seem to have a more prominent neuroregenerative potential. Indeed, in basal conditions they also express neuronal markers. However, it is now well known that the beneficial actions of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules released in the conditioned medium (CM) or in extracellular vesicles (EVs). In this review we focus on the applications of the secretome derived from dental MSCs for neuroregeneration and neuroprotection. The secretomes of different dental MSCs have been tested for their effects for neuroregenerative purposes, and the secretomes of dental pulp stem cells and stem cells from human exfoliated deciduous teeth are the most studied. Both the CM and EVs obtained from dental MSCs showed that they are able to promote neurite outgrowth and neuroprotective effects. Interestingly, dental-derived MSC secretome showed stronger neuroregenerative and neuroprotective effects compared to that obtained from other MSC sources. For these reasons, the secretome obtained from dental MSCs may represent a promising approach for neuroprotective treatments.

Clear Cell Sarcoma of Tendon and Aponeuroses with Excessive Melanin Production – An Unusual Presentation

Clear cell sarcoma of tendons and aponeuroses also called as malignant melanoma of soft parts is a rare tumor of neural crest origin with 70% of them possessing balanced translocation t(12; 22). Approximately 50% of the tumor produces melanin which often shows focal pigmentation or needs special stains to demonstrate melanin. Production of excessive melanin by this tumor is very unusual and very few case reports are available in literature. We report a case of Clear cell sarcoma with excessive melanin production in a 50-year-old female patient involving the left popliteal fossa.

Culturing and Scaling up Stem Cells of Dental Pulp Origin Using Microcarriers

Ectomesenchymal stem cells derived from the dental pulp are of neural crest origin, and as such are promising sources for cell therapy and tissue engineering. For safe upscaling of these cells, microcarrier-based culturing under dynamic conditions is a promising technology. We tested the suitability of two microcarriers, non-porous Cytodex 1 and porous Cytopore 2, for culturing well characterized dental pulp stem cells (DPSCs) using a shake flask system. Human DPSCs were cultured on these microcarriers in 96-well plates, and further expanded in shake flasks for upscaling experiments. Cell viability was measured using the alamarBlue assay, while cell morphology was observed by conventional and two-photon microscopies. Glucose consumption of cells was detected by the glucose oxidase/Clark-electrode method. DPSCs adhered to and grew well on both microcarrier surfaces and were also found in the pores of the Cytopore 2. Cells grown in tissue culture plates (static, non-shaking conditions) yielded 7 × 105 cells/well. In shake flasks, static preincubation promoted cell adhesion to the microcarriers. Under dynamic culture conditions (shaking) 3 × 107 cells were obtained in shake flasks. The DPSCs exhausted their glucose supply from the medium by day seven even with partial batch-feeding. In conclusion, both non-porous and porous microcarriers are suitable for upscaling ectomesenchymal DPSCs under dynamic culture conditions.

Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior.

The Schwann cell

Theodor Schwann, a German physiologist and one of the founding fathers of cellular theory, was the first to hypothesize the association between myelin (the insulating fatty substance surrounding peripheral nerve axons) and the cells that later took his name. In addition to their central role in facilitating the conduction of fast axon potentials, there exist a number of Schwann cell subtypes that are responsible for maintaining normal neural function and signalling at the neuromuscular junction. This chapter provides an overview of the development of the Schwann cells from their neural crest origin and the molecular changes associated with formation of the diverging myelinating and non-myelinating phenotypes. The role of Schwann cells in assisting peripheral nerve axon regeneration is also discussed.

The Role of Chemotherapy in Management of Inoperable, Metastatic and/or Recurrent Melanotic Neuroectodermal Tumor of Infancy—Own Experience and Systematic Review

Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.

Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

Nasal Turbinate Mesenchymal Stromal Cells Preserve Characteristics of Their Neural Crest Origin and Exert Distinct Paracrine Activity

The sources of mesenchymal stromal cells (MSCs) for cell therapy trials are expanding, increasing the need for their characterization. Here, we characterized multi-donor, turbinate-derived MSCs (TB-MSCs) that develop from the neural crest, and compared them to bone marrow-derived MSCs (BM-MSCs). TB-MSCs had higher proliferation potential and higher self-renewal of colony forming cells, but lower potential for multi-lineage differentiation than BM-MSCs. TB-MSCs expressed higher levels of neural crest markers and lower levels of pericyte-specific markers. These neural crest-like properties of TB-MSCs were reflected by their propensity to differentiate into neuronal cells and proliferative response to nerve growth factors. Proteomics (LC–MS/MS) analysis revealed a distinct secretome profile of TB-MSCs compared to BM and adipose tissue-derived MSCs, exhibiting enrichments of factors for cell-extracellular matrix interaction and neurogenic signaling. However, TB-MSCs and BM-MSCs exhibited comparable suppressive effects on the allo-immune response and comparable stimulatory effects on hematopoietic stem cell self-renewal. In contrast, TB-MSCs stimulated growth and metastasis of breast cancer cells more than BM-MSCs. Altogether, our multi-donor characterization of TB-MSCs reveals distinct cell autonomous and paracrine properties, reflecting their unique developmental origin. These findings support using TB-MSCs as an alternative source of MSCs with distinct biological characteristics for optimal applications in cell therapy.

Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review

A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.

Associations of pathological diagnosis and genetic abnormalities in meningiomas with the embryological origins of the meninges

Certain driver mutations and pathological diagnoses are associated with the anatomical site of meningioma, based on which the meninges have different embryological origins. We hypothesized that mutations and pathological diagnoses of meningiomas are associated with different embryological origins. We comprehensively evaluated associations among tumor location, pathological diagnosis (histological type), and genetic alterations including AKT1, KLF4, SMO, POLR2A, and NF2 mutations and 22q deletion in 269 meningioma cases. Based on the embryological origin of meninges, the tumor locations were as follows: neural crest, paraxial mesodermal, and dorsal mesodermal origins. Tumors originating from the dura of certain embryologic origin displayed a significantly different pathological diagnoses and genetic abnormality ratio. For instance, driver genetic mutations with AKT1, KLF4, SMO, and POLR2A, were significantly associated with the paraxial mesodermal origin (p = 1.7 × 10−10). However, meningiomas with NF2-associated mutations were significantly associated with neural crest origin (p = 3.9 × 10–12). On analysis of recurrence, no difference was observed in embryological origin. However, POLR2A mutation was a risk factor for the tumor recurrence (p = 1.7 × 10−2, Hazard Ratio 4.08, 95% Confidence Interval 1.28–13.0). Assessment of the embryological origin of the meninges may provide novel insights into the pathomechanism of meningiomas.