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In this seventh editorial of 2023, we will highlight two disease-relevant manuscripts detailing experiments to (1) investigate the presence and possible role of splenic CD34+stromal cells/telocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of human multiple sclerosis; and (2) to evaluate the potential of using palygorskite clay mineral nanoparticles to stimulate osteogenic differentiation (rather than adipogenesis) in cultured human mesenchymal stem cells as a model for osteoporosis therapeutic treatment.

Splenic telocytes in experimental autoimmune encephalomyelitis

The EAE mouse has served as a model for human multiple sclerosis for a number of years (Constantinescu et al. 2011). Multiple sclerosis is a debilitating autoimmune disease, with multiple complex genetic and environmental components, in which inflammatory reactions result in oligodendrocyte damage and subsequent demyelination (Dobson and Giovannoni 2019). Given this disease etiology, the role of inflammation and immune organs is of paramount interest in seeking therapeutic interventions. Immune organs, such as the spleen, contain a number of highly interacting cell types involved in pathophysiologic mechanisms and responses. Amongst these myriad cell types, telocytes have emerged as potentially playing an essential role in the overall immune microenvironment (Aleksandrovych et al. 2022). Telocytes are interstitial cells of mesenchymal origin previously identified in multiple tissue organs, and described by various names and terminologies, including “interstitial Cajal-like cells” (Popescu and Faussone-Pellegrini 2010), illustrating the conundrum of whether they should be considered one homogeneous cell type, or rather are representative of multiple phenotypically similar cell types. To avoid future confusion, in 2010 Popescu and Faussone-Pellegrini (2010) proposed the term “telocytes” (from the Greek “telos” for “power to decide”) be adopted to describe these cells based upon specific phenotypic characteristics. In this issue of the journal, Dama et al. (2023) have investigated the potential role of splenic telocytes in immune processes in the EAE mouse model. To identify the distribution of telocytes (which they refer to as CD34+ SCs/TC; stromal cells/telocytes) versus other potentially confounding cell types, they have relied upon multiplex immunohistochemical staining patterns and ultrastructural characterization by transmission electron microscopy. Using five different immunohistochemical antibody staining combinations, they found that telocytes in the spleen of the EAE mouse model could be phenotypically characterized as immunohistochemically positive for CD34, c-kit, and vimentin (indicating that they are not of fibroblastic origin). These cells were found to be increased in number in the spleen from EAE mice compared with those obtained from wild type (WT) animals. Additional immunostaining experiments showed that this increase in the number of telocytes was accompanied by a concomitant increase in macrophages, hematopoietic cells, and pluripotent stem cells in the same splenic regions. The CD34+ SCs/TC cells were also immunocytochemically negative for CD31 and tryptase, ruling them out as endothelial cells and mast cells. Ultrastructural characterization of telocytes in the spleen by transmission electron microscopy identified features distinguishing them from fibroblasts. Telocytes were characterized as cells with small, spindle-shaped bodies accompanied by protruding long cellular processes called telopodes. These cells were seen in close proximity with lymphocytes, reticular cells, macrophages, endothelial cells, and erythrocytes in the splenic white pulp. On the basis of their results, the authors propose that telocytes in EAE mouse spleen may be involved in modulating the immune response via the recruitment of macrophages and the proliferation of hematopoietic and pluripotent stem cells to assist in tissue repair following an inflammatory injury. In this light, the authors propose that telocytes combined with stem cell transplantation might provide a potential therapeutic treatment for autoimmune and inflammatory disease.

Attacking osteoporosis with clay

In their comprehensive reviews, Debbage and Jaschke (2008) and Thurner and Debbage (2018) have outlined the remarkable properties of various types of nano-sized particles and their diverse biomedical applications. For their use in disease-related processes, the intrinsic or functionalized surface properties of such small particles are of critical importance. In continuation of their studies on nanoclays as mediators of cell–cell adhesion (Abduljauwad et al. 2021; Ahmed and Abduljauwad 2016), Abduljauwad and coworkers (2023) have now evaluated the potential of palygorskite clay mineral microparticles to stimulate osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro. The rationale behind their studies was that the charged, lath-like clay microparticles through interaction with charged surfaces would restore adhesion between hMSCs and the niche. For treatment of hMSCs in vitro, clay particles were fractionated according to size to obtain particles smaller than 2.5 μm. Such particles were embedded in a thin layer of VitroGel 3D hydrogel, which was used to coat 24-well cell culture plates. Alkaline phosphatase activity as an indicator of osteogenic differentiation of hMSCs was measured after 14 days, and Alizarin Red S staining to detect calcium deposits after 21 days. Furthermore, the following osteogenic differentiation markers were evaluated by quantitative RT-PCR: ALPL (tissue nonspecific alkaline phosphatase), BGLAP (osteocalcin), Col1A1, DMP1 (dentin matrix acidic phosphoprotein 1), IBSP (integrin binding sialoprotein), RUNX1 (Runt-related transcription factor 1), SP7 (osterix) and SPP1 (secreted phosphoprotein 1), and found to be unchanged. Treatment of cultured hMSCs with clay particles in suspension had no influence on ALP activity relative to incubation in osteogenic differentiation medium. In contrast, a significant increase in ALP activity was detected after culture on VitroGel 3D hydrogel-enclosed clay microparticles. Calcium deposits, as detected by Alizarin Red S, were increased in hMSC cultures grown in osteogenic differentiation medium, further increased when the osteogenic differentiation medium contained clay microparticles, and finally were most intensely increased when VitroGel 3D hydrogel-enclosed clay microparticles were applied. The authors noted that “when cells were cultured on clay microparticle-embedded hydrogels… some of the larger microparticles adhered to the cells. This implies that the hMSCs can extract the microparticles from the hydrogel.” Altogether, the authors propose that the charged palygorskite clay microparticles interact via attractive (electrostatic) forces with both the hMSCs and their environment (niche). The resulting different types and strengths of adhesion probably restore the osteogenic differentiation potential of hMSCs.