Survivin Is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function

Abstract

Although mesenchymal stromal cells (MSCs) have significant potential in cell-based therapies, little is known about the factors that regulate their functions. While exploring regulatory molecules potentially involved in MSC activities, we found that the endogenous multifunctional factor Survivin is essential for MSC survival, expansion, lineage commitment, and migration. Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony-forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion. Survivin is also required for the MSC proliferative responses to basic fibroblast growth factor and platelet derived growth factor. In a wound healing model, Survivin inhibition results in suppression of MSC migration to the wound site. In addition, loss of Survivin in MSCs compromises their hematopoiesis-supporting capacity. These results demonstrate that Survivin is a key regulator of mouse and human MSC function, and suggest that targeted modulation of Survivin in MSCs may have clinical utility to enhance MSC recovery and activity following insult or stress. STEM CELLS 2018;36:123-129 SIGNIFICANCE STATEMENTResults of this study demonstrate that Survivin is essential for mouse and human mesenchymal stromal cell (MSC) survival, proliferation, and differentiation. The ability to enhance MSC expansion/survival by growth factor (i.e., basic fibroblast growth factor or platelet derived growth factor)-mediated Survivin modulation represents a novel therapeutic strategy particularly for hematopoietic regeneration after clinical transplantation, where HSC supportive niche forming MSCs are severely depleted as a consequence of irradiation exposure.

BIRC5 Expression Is Regulated in Uterine Epithelium during the Estrous Cycle

“…As a member of the IAP family, Birc5 is expressed in various cells including hematopoietic cells, immune cells and vascular endothelial cells, and mesenchymal stromal cells [4,17,18]. Additionally, Birc5 plays a role in regulating cell proliferation and survival.…”

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

“…The expression is observed in all stages of interphase with exceptionally high expression in G2/M phase. Increased survivin expression protects MSCs that form HSCs supportive niche depleted post irradiation exposure [37]. The protein has been linked to survival in these cells subjected to stress induced by heat shock, UV or etoposide as well [38].…”

Antiapoptotic Molecule Survivin in Transplantation: Helpful or Harmful?

“…Furthermore, it has been shown that survivin inhibition in mouse and human bone marrow results in fewer MSC and clonogenic colony forming unit fibroblasts, whereas survivin overexpression in MSC promotes their proliferation; moreover, survivin inhibition in MSCs reduces their hematopoiesis-supporting capacity. According to the considerable role of MSCs in engraftment and maintenance of hematopoietic stem cell transplantation (HSCT), survivin-expressing MSCs seem to promote HSCT outcome [ 27 ]. In addition, erythrocytes have been demonstrated to be significantly dependent on survivin in their proliferation and maturation process, as heterozygous deletion of survivin in mice is accompanied by decreased number of enucleated erythrocytes and insufficient erythropoiesis while its complete deletion causes death [ 28 ].…”