Research output: Contribution to journal › Article › Academic › peer-review
Nuclear shape, protrusive behaviour and in vivo retention of human bone marrow mesenchymal stromal cells is controlled by Lamin-A/C expression. / Dorland, Yvonne L; Cornelissen, Anne S; Kuijk, Carlijn et al.
In: Scientific reports, Vol. 9, No. 1, 07.10.2019, p. 14401.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Nuclear shape, protrusive behaviour and in vivo retention of human bone marrow mesenchymal stromal cells is controlled by Lamin-A/C expression
AU - Dorland, Yvonne L
AU - Cornelissen, Anne S
AU - Kuijk, Carlijn
AU - Tol, Simon
AU - Hoogenboezem, Mark
AU - van Buul, Jaap D
AU - Nolte, Martijn A
AU - Voermans, Carlijn
AU - Huveneers, Stephan
PY - 2019/10/7
Y1 - 2019/10/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85073064900&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31591420
U2 - 10.1038/s41598-019-50955-x
DO - 10.1038/s41598-019-50955-x
M3 - Article
C2 - 31591420
VL - 9
SP - 14401
JO - Scientific reports
JF - Scientific reports
SN - 2045-2322
IS - 1
ER -
ID: 7087101