On the other hand, single-cell RNA sequencing (scRNAseq) of cells traced with either LepR or vascular endothelial cadherin (VE-Cadherin, also known as CD144) revealed that they do not express (Tikhonova et al., 2019). on the basis of various genetic markers (i.e., Nestin, Leptin receptor, Gremlin1, Cathepsin-K, etc.). However, the niches in which these cells reside have received less attention. Here, we summarize the current scientific literature on stem cell niches for the SSPCs identified so far and discuss potential factors and environmental cues of importance in these niches cultures, as well as in diffusion chambers implanted into mice (Caplan, 1991). It should be emphasized here that this dogma in the 1980s and early 1990s was that the adult body only contained one type of stem cells, namely, hematopoietic stem cells. Accordingly, these initial discoveries of bone marrow stromal stem cells/MSCs were recognized and appreciated primarily by investigators interested in experimental hematology. Rabbit Polyclonal to TIGD3 However, this was changed by the publication by Pittenger (1999) of a protocol for Sitaxsentan the isolation, phenotypic characterization and growth of human MSCs, which was well received in the atmosphere of enjoyment generated by the discovery of human embryonic stem cells. Unfortunately, during subsequent decades the pronounced Sitaxsentan heterogeneity of MSCs, in combination with the wide variety of experimental approaches employed to isolate and culture these cells, led to confusion in this field. It also became clear that the term mesenchymal stem cells is usually inappropriate, since it does not Sitaxsentan reflect their properties accurately (Dominici et al., 2006; Bianco et al., 2008). Even Caplan, the inventor of this term, made pleas that it Sitaxsentan be changed (Caplan, 2010, 2017). In 2006 the International Society of Cellular Therapies recommended the terminology multipotent mesenchymal stromal cells instead, defining these as clonogenic, multipotent, self-renewing cells that express CD105, CD73, and CD90, but not CD45, CD34, CD14, CD11b, CD79, or HLA-DR, and are capable of osteogenic, chondrogenic and adipogenic differentiation (Dominici et al., 2006). Nonetheless, the term MSCs is usually utilized so widely by researchers around the globe that it is unclear when, or even if this terminology will be clarified, an issue that continues being discussed (Bianco and Robey, 2015; Caplan, 2017; Ambrosi et al., 2019). In the present review we focus almost exclusively on characterization of MSCs, which are often referred to as skeletal stem cells (SSCs) (Bianco and Robey, 2015; Ambrosi et al., 2019). Since in many cases these cell populations are characterized on the basis of genetic markers which actually label heterogenous populations (Debnath et al., 2018; Tikhonova et al., 2019), below we will use the term skeletal stem and progenitor cells (SSPCs). In recent years several types of SSPCs at different locations within the skeleton and with different functions and markers have been described (Sacchetti et al., 2007; Mndez-Ferrer et al., 2010; Ding et al., 2012; Greenbaum et al., 2013; Zhou B.O. et al., 2014; Chan et al., 2015; Li et al., 2017; Mizuhashi et al., 2018, 2019; Newton et al., 2019). However, our understanding of the local microenvironment in which these various SSPCs reside and the factors involved in regulating their behavior is still evolving. Below, on the basis of what is known to date, we make some suggestions concerning the nature of each particular niche. We have arranged our comments in the order of the following anatomical locations: articular cartilage, epiphyseal cartilage, periosteum, adult endosteal compartment and developing endosteal Sitaxsentan compartment. SSPCs in the Articular Cartilage and their Maintenance The superficial zone of articular cartilage contains chondroprogenitors capable of generating chondrocytes, both (Dowthwaite et al., 2004) and (Kozhemyakina et al., 2015) and also capable of reconstituting the entire articular cartilage (i.e., the middle and deep zone chondrocytes) in postnatal mice (Li et al., 2017). These cells have the following characteristics: (i) Expression of several markers commonly utilized for the identification of.