Nanotubular Crosstalk with Distressed Cardiomyocytes Stimulates the Paracrine Repair Function of Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell-to-cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF-1a, and MCP-3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of na€ ıve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies. STEM CELLS 2014;32:216-230

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

“…Thus, a previous work revealed increased regenerative support during nanotubular cross-talk between MSC and damaged cardiomyocytes [60]. Intercellular transport via nanotubes requires actin microfilaments to transmit traction and contraction forces that can be blocked by cytochalasin D for inhibition of actin polymerization.…”

Rescue of Brain Function Using Tunneling Nanotubes Between Neural Stem Cells and Brain Microvascular Endothelial Cells

“…TNTs have been identified in various cell types, where they form direct cell-to-cell channels [12]. Several in vitro studies have demonstrated that these structures facilitate the exchange of molecules, RNA, proteins, and especially mitochondria, which is reported most frequently [13].…”

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…Cell refinement can be achieved, for instance, by density centrifugation [13], magnetic-(MACS) [26,33] or fluorescence-activated cell sorting (FACS) [99] or by pre-in vitro priming [8,13,27,33,58,99,100]. Density centrifugation is often used to isolate mononuclear cells (BMMNC) from BM cell suspension [13,75], while MACS and FACS achieve a higher degree of selectivity by picking up cells according to their surface markers (cluster of differentiation, CD).…”

“…Another reported strategy for cell refinement is the enrichment of BMMNC with higher in vitro migratory capacity towards the chemokine SDF-1, which also appears to be correlated with higher proliferative, pro-angiogenic and anti-fibrotic properties [13]. Cells can also be preconditioned by induction of a cardiac program within a cardiomyogenic culture medium [8] or the co-culture of ADMSC with distressed CMs, with the purpose of acclimatizing cells to the environment found in injured myocardia [100].…”

“…After being administered, cells can be nearly gone as soon as 1 to 3 days after transplantation [44,45]. However, some authors reported signs of stem cell survival up to 1 week [8,16,60,100,104], 1 month [14,18,23,27,30,37,46,52,67,105] and, most strikingly, up to 1 year [26]. When retained cells are quantified, we find that less than 3% of the stem cells survive more than 4 weeks [59,70] and that percentage drops to levels below 1% when the assessment is made 16 weeks after transplantation [106].…”