Stem Cells Dev.2015 Jan;24(1):115-131

Placental mesenchymal stromal cells derived from blood vessels or avascular tissues: What is the better choice to support endothelial cell function?

Julia König1,2*, Gregor Weiss1*, Daniele Rossi3, Karin Wankhammer1, Andreas Reinisch4, Manuela Kinzer1, Berthold Huppertz1, Dagmar Pfeiffer1,5, Ornella Parolini3, Ingrid Lang1.

* Julia König and Gregor Weiss contributed equally.

1 Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria

2 Current address: School of Health and Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

3 Centro di Ricerca E.Menni, Fondazione Poliambulanza, Brescia, Italy

4 Stem Cell Research Unit, Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

5 Center of Biomedical Technology, Danube University Krems, Austria

 

Contact:

Prof. Ingrid Lang,

Institute of Cell Biology, Histology and Embryology

Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria

Telephone: 0043-316-380 7607; Fax: 0043-316-380 9625

E-mail: ingrid.lang@medunigraz.at

 

ABSTRACT

Mesenchymal stromal cells (MSC) are promising tools for therapeutic revascularization of ischemic tissues and for support of vessel formation in engineered tissue constructs. Recently, we could show that avascular-derived MSC from placental amnion release soluble factors that exhibit survival-enhancing effects on endothelial cells. We hypothesize that MSC derived from placental blood vessels might have even more potent angiogenic effects. Therefore, we isolated and characterized MSC from placental chorionic blood vessels (bv-MSC) and tested their angiogenic potential in comparison to amnion-derived avascular MSC (av-MSC).

Bv-MSC express a very similar surface marker profile compared to av-MSC and could be differentiated towards the adipogenic and osteogenic lineage. Bv-MSC exert immunosuppressive properties on peripheral blood mononuclear cells suggesting that they are suitable for cell transplantation settings. Conditioned medium from av-MSC and bv-MSC significantly enhanced endothelial cell viability, whereas only conditioned medium from bv-MSC significantly increased endothelial cell migration and network formation (Matrigel assay). Angiogenesis array analysis of av- and bv-MSC-conditioned medium revealed a similar secretion pattern of angiogenic factors including angiogenin, interleukin-6 and -8, TIMP-1&2. ELISA analysis showed that, in contrast to av-MSC, bv-MSC secreted VEGF. In direct co-culture with bv-MSC, endothelial cells showed a significantly increased formation of vessel-like structures compared to av-MSC.

With regard to therapeutic treatment, bv-MSC and particularly their conditioned medium might be valuable to stimulate angiogenesis especially in ischemic tissues. Av-MSC and their conditioned medium could be beneficial in conditions when it is required to promote the survival and stabilization of blood vessels without the risk of unmeant angiogenesis.

 

SUPPLEMENTARY

MSC are commonly isolated from bone marrow or other adult tissues such as adipose tissue. This complicates their use due to invasive isolation methods and impaired proliferation and differentiation capacities, which possibly depend on the age and disease stage of the donors. As appealing alternative cell types, we isolated MSC from postnatal tissues such as placental blood vessels (bv-MSC) and placental avascular amnion (av-MSC). We could recently show that av-MSC exhibit beneficial, survival-enhancing effects on endothelial cells in vitro [1] and exert positive effects on capillary formation in a mouse model in vivo [2]. In the current study we hypothesize that blood vessel-derived MSC might have even more potent angiogenic effects than avascular-derived MSC.

 

Fig Lang 300 dpi

 

We examined similarities and differences of both MSC types and their impact on endothelial cells (EC) (Figure). Both av-MSC and bv-MSC have similar surface markers, adipogenic and osteogenic differentiation potential, are immunosuppressive, form networks on Matrigel, attach to endothelial networks and enhance the viability of endothelial cells. Contrary to av-MSC, bv-MSC secrete the vascular endothelial growth factor VEGF; they enhance endothelial cell migration and induce endothelial cells to form vessel-like structures.

In summary, bv-MSC, which are closely located to blood vessels in situ, were more potent in inducing angiogenesis, as shown by a significant effect on endothelial network formation. This is probably the result of a higher secretion of angiogenic cytokines, especially of VEGF.

The advantage of both of these placenta-derived MSC is that they are available in large supply and can be isolated non-invasively. They are immunologically well tolerated, do not form tumors in the recipient and are cells of fetal origin [1,3]. The combination of their immunomodulatory and endothelial cell supporting properties makes them promising tools for blood vessel reconstruction.

With regard to a therapeutic treatment, bv-MSC might be valuable to stimulate angiogenesis especially in ischemic tissues, while av-MSC could be beneficial in conditions when it is required to promote the survival and stabilization of blood vessels without the risk of unmeant angiogenesis.

 

REFERENCES

  1. Konig J, B Huppertz, G Desoye, O Parolini, JD Frohlich, G Weiss, G Dohr, P Sedlmayr and I Lang. (2012). Amnion-derived mesenchymal stromal cells show angiogenic properties but resist differentiation into mature endothelial cells. Stem Cells Dev 21:1309-1320.
  2. Kinzer M, K Hingerl, J König, A Reinisch, D Strunk, B Huppertz, I Lang. (2014). Mesenchymal stromal cells from the human placenta promote neovascularization in a mouse model in vivo. Placenta 35:517-9.
  3. Parolini O, F Alviano, GP Bagnara, G Bilic, HJ Buhring, M Evangelista, S Hennerbichler, B Liu, M Magatti, N Mao, T Miki, F Marongiu, H Nakajima, T Nikaido, CB Portmann-Lanz, V Sankar, M Soncini, G Stadler, D Surbek, TA Takahashi, H Redl, N Sakuragawa, S Wolbank, S Zeisberger, A Zisch and SC Strom. (2008). Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells 26:300-311.

 

FUNDING

This work was supported by the Franz-Lanyar-Foundation (Project # 363). Gregor Weiss was supported by the Austrian Science Fund (FWF, Project P24739).

 

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