Improved Autograft Survival of Mesenchymal Stromal Cells by Plasminogen Activator Inhibitor 1 Inhibition

Abstract

Mesenchymal stromal cells (MSCs) display robust reparative properties through their ability to limit apoptosis, enhance angiogenesis, and direct positive tissue remodeling. However, low in vivo survival of transplanted cells limits their overall effectiveness and significantly affects their clinical usage. Consequently, identifying strategies to improve cell survival in vivo are a priority. One explanation for their low survival is that MSCs are often transplanted into ischemic tissue, such as infarcted myocardium, where there is poor blood supply and low oxygen tension. Therefore, we examined how MSCs respond to a hypoxic, nutrient-poor stress environment to identify trophic factors that could be manipulated in advance of MSC transplantation. Combining microarray and proteomic screens we identified plasminogen activator inhibitor 1 (PAI-1) as one factor consistently upregulated in our in vitro ischemia-mimicking conditions. Subsequent genetic and chemical manipulation studies define PAI-1 as a negative regulator of MSC survival in vivo. Mechanistically, MSC-derived PAI-1 does not alter MSC survival through a plasmin-dependent mechanism but rather directly impacts on the adhesiveness of MSCs to their surrounding matrices. Thus we can conclude that posttransplantation, PAI-1 negatively impacts MSC survival by promoting anoikis via matrix detachment. STEM

Plasminogen Activator Inhibitor-1 Controls Bone Marrow-Derived Cells Therapeutic Effect Through MMP9 Signaling: Role in Physiological and Pathological Wound Healing

“…Our results are also in accordance with other findings combining microarray and proteomic screenings revealing that PAI-1 is a negative regulator of the survival of mesenchymal stromal cells (MSCs) in vivo [27]. MSC-derived PAI-1 does not alter MSC survival through a plasmin-dependent mechanism but rather directly impacts on the adhesiveness of MSCs to their surrounding matrices.…”

“…MSC-derived PAI-1 does not alter MSC survival through a plasmin-dependent mechanism but rather directly impacts on the adhesiveness of MSCs to their surrounding matrices. Thus, PAI-1 appears to act as an antiadhesive molecule for MSCs, and it likely will have a negative effect in vivo when MSCs are directly implanted in animals after ischemia [27].…”

Anoikis: an emerging hallmark in health and diseases

“…For example, plasminogen activator inhibitor 1 is secreted by transplanted cells, leading to a decrease of their ECM contacts, leading to anoikis. In keeping with this, the inhibition of plasminogen activator inhibitor 1 improves autograft survival of bone marrow-derived cells [170].…”

Enhancing the efficacy of mesenchymal stem cell therapy

“…Rapid loss of the implanted MSCs has been frequently observed and may be caused in part by hypoxic stress, which triggers apoptosis [62][63][64] . The bone marrow environment contains oxygen tensions ranging from 1% to 7%.…”

“…Rapid loss of the injected cells is perceived as a major hurdle in stem cell therapy [63,64,77] and may be caused in part by inadequate ECM engagement. Expression of chemokines and their receptors is known to be regulated by cytokines and this phenomenon has been explored to facilitate MSC engraftment after cell implantation [78,79] .…”