Our coculture experiments demonstrated that all three MSCs s
Our coculture experiments demonstrated that all three MSCs showed a similar low in vitro proliferation; for most patients coculture of all three MSCs with primary human AML colorimetric did not alter MSC proliferation but a minor increase in the proliferation was seen for a minority of patients. No or only minor effects on MSC proliferation were also seen when they were cultured with exogenous cytokines or AML supernatants. These observations suggest that the growth-enhancing effect of primary AML cells on MSCs depends on the overall intercellular crosstalk. It should in addition be emphasized that the MSC growth enhancement was observed for most patients despite the wide variation in cytokine release between patients both in AML cultures and AML–MSC cocultures.
Coculture of MSCs with primary AML cells especially altered the MSC expression of genes involved in TLR-initiated signaling (i.e. genes downstream to the receptors), regulation of NFκB and chemokine/interleukin expression (Fig. 4 and Supplementary Table 3). These three components form an interacting system at different levels of the cells (Bruserud et al., 2007). TLR receptors show transactivation with G-protein coupled receptors (e.g. chemokine receptors) (Abdulkhalek et al., 2012), NFκB is an important downstream target of TLR-initiated signaling and NFκB is in addition an important regulator of chemokine expression/release in various human cells, including primary AML cells. Therapeutic targeting of the NFκB system thus seems to represent an opportunity to modulate the local AML-supporting cytokine network in the bone marrow through inhibition of cytokine release both by the leukemic cells and normal stromal cells.
Ito et al. (2014) demonstrated that MSCs could support the growth of AML cells in cocultures, and our present study shows that there is a bidirectional crosstalk between AML cells and MSCs as the MSC characteristics were altered in our transwell cocultures. However, it is not known whether the cytokine network alone mediates an AML-supporting bidirectional crosstalk between mesenchymal and leukemic cells because the study by Ito et al. questioned the importance of the cytokine network and emphasized the importance of direct cell–cell contact for the MSC-associated growth enhancement of the AML cells (Ito et al., 2014).
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Introduction The induction of cellular plasticity has emerged as a powerful tool for regenerative medicine (Yamanaka and Blau, 2010; Nie et al., 2012; Katsuyama and Paro, 2011). Regeneration seen in a wide range of non-mammalian vertebrates, such as urodele amphibians and teleost fish provides important information about natural mechanisms of using cellular plasticity for renewing large body parts (Brockes and Kumar, 2002; Gemberling et al., 2013). A crucial question for the field of regenerative medicine is whether urodele regeneration can be recapitulated in mammalian cells. Studies on amphibian or fish regeneration identified reversal and plasticity of the differentiated state as a major mechanism to produce stem cell-like cells during regeneration (Jopling et al., 2010; Echeverri et al., 2001; Kragl et al., 2009). This process, classically called dedifferentiation, reprograms differentiated cells at the wound site back to a progenitor stage, which can then proliferate and replace the missing tissue with appropriate patterning (Stoick-Cooper et al., 2007). Dedifferentiation has been best characterized in salamander muscle cells. It has been shown that upon signals produced in the regenerating tissue, multinucleated postmitotic differentiated myotubes can reverse their differentiated state and give rise to proliferating progenitors (Lo et al., 1993; Kumar et al., 2000; Sandoval-Guzmán et al., 2014). To date, there is not any convincing evidence demonstrating dedifferentiation occurring physiologically in mammalian muscles. Therefore, an intriguing question is whether this process could be engineered into mammalian muscle.