Abstract
Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types.
Highlights
Mesenchymal stem cells (MSC) are considered as a potential therapy for a wide variety of degenerating and immunological disorders (Giordano et al, 2007; Reinders et al, 2010; Salem and Thiemermann, 2010)
The old dogma that administered MSC engraft and differentiate in specialized cell types has been abandoned, whereas the proposition that the effects of MSC are mediated via the secretion of trophic and immunoregulatory factors has gained in popularity
In the present study we demonstrated that MSC accumulate in the lungs within the first few hours after intravenous infusion
Summary
Mesenchymal stem cells (MSC) are considered as a potential therapy for a wide variety of degenerating and immunological disorders (Giordano et al, 2007; Reinders et al, 2010; Salem and Thiemermann, 2010). The encouraging results in such models have initiated the translation of MSC therapy in clinical trials in a range of disorders, including graft versus host disease, inflammatory bowel disease, and cardiac infarct (Le Blanc et al, 2008; Hare et al, 2009; Duijvestein et al, 2010). While MSC have the capacity to differentiate into multiple cell types (Pittenger et al, 1999; Long et al, 2005), secrete growth factors that stimulate the proliferation and differentiation of other cells (Lee et al, 2011), and inhibit the proliferation of immune cells in vitro via the secretion of antiinflammatory factors (Di Nicola et al, 2002), it is unknown whether these mechanisms are operational after administration of MSC. There is controversy about the localization and persistence of MSC in the body after administration. The route of administration is an important factor determining the fate of MSC. Administration of MSC via alternative routes leads to detainment of MSC in other filtering organs. MSC administered via the portal vein are found in the liver (Shi et al, 2010), while MSC administered in tissues like muscle, spine, and fat pads remain present locally up to several weeks (Boulland et al, 2012; Hu et al, 2012; Nam et al, 2012)
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