Abstract
Culture expanded mesenchymal stromal cells (MSCs) are being extensively studied for therapeutic applications, including treatment of graft-versus-host disease, osteogenesis imperfecta and for enhancing engraftment of hematopoietic stem cells after transplantation. Thus far, clinical trials have shown that the therapeutic efficiency of MSCs is variable, which may in part be due to inefficient cell migration. Here we demonstrate that human MSCs display remarkable low migratory behaviour compared to other mesodermal-derived primary human cell types. We reveal that specifically in MSCs the nucleus is irregularly shaped and nuclear lamina are prone to wrinkling. In addition, we show that expression of Lamin A/C is relatively high in MSCs. We further demonstrate that in vitro MSC migration through confined pores is limited by their nuclei, a property that might correlate to the therapeutic inefficiency of administered MSC in vivo. Silencing expression of Lamin A/C in MSCs improves nuclear envelope morphology, promotes the protrusive activity of MSCs through confined pores and enhances their retention in the lung after intravenous administration in vivo. Our findings suggest that the intrinsic nuclear lamina properties of MSCs underlie their limited capacity to migrate, and that strategies that target the nuclear lamina might alter MSC-based cellular therapies.
Highlights
Bone marrow-derived mesenchymal stromal cells (MSCs1), are promising candidates for cellular therapies because of their regenerative and immunomodulatory potential[2,3,4,5]
Tracking of single cell migration showed that the average migration velocity of adult bone marrow-derived MSC (ABMSC) under these conditions was 0.1 μm/min and of fetal human bone marrow-derived MSC (FBMSC) was 0.24 μm/min (Fig. 1A and Supplemental Movie 1), which is similar to migration velocities of MSCs reported previously in literature[36,37]
The average migration speed of human umbilical vein endothelial cells (HUVECs) and human fibroblasts was higher compared to ABMSC (Fig. 1A and Supplemental Movie 1) on these substrates
Summary
Bone marrow-derived mesenchymal stromal cells (MSCs1), are promising candidates for cellular therapies because of their regenerative and immunomodulatory potential[2,3,4,5]. To explore approaches to improve MSC-based cellular therapies, previous research has focused on increasing the expression of chemokine receptors or decreasing availability of adhesion molecules (reviewed in[18,19]). Most of these migration-promoting methods have www.nature.com/scientificreports/. Migration through tissue and sensing of the microenvironment tightly depends on the rigidity, shape and anchoring of the nucleus within the cytoskeleton[12,27,28,29] These properties are controlled by the nuclear lamina proteins Lamin A/C and Lamin B130 and through coupling of the nuclear envelope to the cytoskeleton via the LINC complex[31]. We show that silencing expression of Lamin A/C promotes the protrusive capacity of MSCs, suggesting that targeting of the MSC nuclear envelope might change therapeutic efficiency of MSCs
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