This in turn reduces the inflammatory response in the tissues. 7.4. and the experimental therapeutic applications conducted to treat multiple diseases in experimental animal models in vivo. G-MSCs show remarkable tissue reparative/regenerative potential, noteworthy immunomodulatory properties, and primary experimental therapeutic applications of G-MSCs are very promising, pointing at future biologically based therapeutic techniques, being potentially superior to conventional clinical treatment modalities. 1. Introduction The human periodontium, the tooth supporting and investing organ, comprising the alveolar bone, the periodontal ligament, the root cementum, and the gingiva develops and functions as one unit. The majority of the periodontal tissues originate embryonically from the neural crest ectomesenchyme . The gingiva, histologically composed of epithelium and connective tissue, constitutes a distinctive as well as a pivotal component of the human periodontium developmentally and anatomically, surrounding the necks of the teeth and investing the tooth-bearing alveolar bone. One of the gingiva’s renowned characteristics is its notable wound healing and regenerative aptitude, with a fast reconstitution of tissue architecture following injury or excision with little, if any, evidence of scarring . This tissue is usually easily accessible and is often resected during standard surgical procedures, including dental crown lengthening and multiple periodontal surgeries, with minimal discomfort to the patient . Developmentally, the craniofacial ectomesenchyme is derived from the neural crest and the mesoderm. The multipotent cranial neural crest cells (CNCCs) migrate ventrolaterally to reside in the first branchial arches, starting from the four-somite stage, giving rise to mesenchymal structures in the craniofacial region, including neural tissues, cartilage, bone, and teeth [4, 5]. In addition to a common neural crest ectomesenchymal origin, lined by ectoderm for all those oral soft tissues, the tooth-investing gingival connective tissue shows a unique developmental origin, arising partly from the perifollicular mesenchyme (the outer layer of the dental follicle) , as well as partly from the dental follicle proper (the inner layer of the dental follicle) , from which dental follicle stem/progenitor cells (DFSCs) were isolated . Periodontal ligament cells , originating themselves from the dental follicle proper  and from which a subpopulation of periodontal ligament stem/progenitor cells (PDLSCs) has been characterized , further contribute to its development. In addition, earlier studies demonstrated LEFTY2 the presence of fibroblasts stemming from the inner layer of the dental follicle in the free gingival lamina propria at the cementoenamel junction  and further suggested that this dentogingival fiber system originates in part from the periodontal ligament cells  (Physique 1). This developmental contribution, provided by the dental follicle proper and the periodontal ligament cells to the perifollicular mesenchyme, accounts for an anatomical distinctiveness of the tooth-investing gingival connective tissue compared to other oral mucosal tissues . Open in a separate window Physique 1 Schematic drawing of the oral tissues contributing to the developmental origin of human gingival lamina propria. DFSCs: dental follicle stem cells, G-MSCs: gingival mesenchymal stem/progenitor cells, PDLSCs: periodontal ligament stem cells. The numerous functions of adult gingival wound fibroblasts CM-272 and their variance in responsiveness to growth factors as well as their capacity to produce particular extracellular matrix proteins during healing validated an earlier hypothesis that gingival connective tissue fibroblasts embody a heterogeneous cell population [8, 10C13]. It further implied the presence of a resident population of adult mesenchymal stem/progenitor cells, giving rise to these heterogeneous cells. Previous studies described the isolation of progenitors from oral soft tissues, including the incisive papillae and rugae area of the palate , the maxillary tuberosity , the oral mucosa , the whole , the attached and free [3, 18, 19], and the hyperplastic gingiva . Clinically, special attention is placed around the gingiva as a source mesenchymal stem/progenitor cells, representing the most abundant, accessible, and conservative minimally invasive source for stem/progenitor cells’ isolation from the oral cavity  (Physique 2). Open in a separate window Physique 2 Sources of oral stem/progenitor cells isolated. DFSCs: dental follicle stem cells, G-MSCs: gingival mesenchymal stem/progenitor cells, PDLSCs: periodontal CM-272 ligament stem cells, SHEDs: stem cells from the human exfoliated deciduous teeth, DPSCs: dental pulp stem cells, BM-MSCs: bone marrow mesenchymal stem cells, and SCAP: stem cells from the apical papilla. 2. Gingival Mesenchymal Stem/Progenitor Cells’ (G-MSCs) Isolation A wide array of designations currently exist for mesenchymal stem/progenitor cells isolated from the gingival lamina propria, including gingiva-derived mesenchymal stem/stromal cells (G-MSCs) , gingival-tissue-derived stem cells (GT-MSCs) , gingival multipotent progenitor cells (GMPCs) , and gingival margin-derived stem/progenitor cells . For clarity, the term gingival mesenchymal stem/progenitor cells (G-MSCs) will CM-272 be used to uniformly designate these cells in the present review. Studies reporting on techniques for G-MSCs’ isolation surgically obtained gingival tissue samples from human subjects or animals via.