Paper of the Month: Proangiogenic Paracrine Effects of Stem Cells

This paper was selected because the findings by the Lindner team demonstrate beautifully the promise of stem cell therapy to improve vascular function revealed through powerful ultrasound based molecular imaging techniques.

- - Mary Stenzel-Poore, Ph.D.
Senior Associate Dean for Research

March 27, 2013

Dr. LindnerThe number of severely symptomatic patients with coronary and peripheral artery disease who are not candidates for revascularization therapy because of comorbidities and/or diffuse distribution of disease is steadily growing. Therapy with pro-angiogenic stem cells can improve tissue perfusion, although the exact mechanisms by which they promote vascular remodeling are unknown and are important for optimization of therapy. There is increasing evidence that stem cells enhance vascular remodeling in part through paracrine effects (local effects on native cells).

Using molecular imaging, Jonathan Lindner, M.D., a professor in the Knight Cardiovascular Institute, whose work specializes in non-invasive cardiovascular imaging, and team of investigators, tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPC) promotes recovery of blood flow through the recruitment of subpopulation of pro-angiogenic monocytes.

In their study, the team used contrast ultrasound perfusion in a murine ischemic limb model to demonstrate that multipotential adult progenitor cells given intramuscularly increased microvascular blood flow and volume over the course of 21 days.

"On a structural level, the improvement in flow was due to arteriolar remodeling which decreases microvascular resistance and increases the spatial distribution of flow within the limb tissues," said Dr. Lindner. "Intravital microscopy which allows direct visualization of the living microcirculation showed that MAPCs do not themselves grow into new blood vessels or engraft into blood vessels. Rather, they migrate to a perivascular location where they promote the local recruitment of leukocytes."

Ultrasound molecular imaging and histology was used to better understand this process and to evaluate the paracrine effects of the MAPCs.

The team's study indicates that MAPCS act to: (1) stimulate the expression of endothelial cell adhesion molecules that are necessary for monocyte adhesion and transmigration, and (2) enhance migration of a specific pro-angiogenic population of monocytes. These effects persisted for at least 21 days despite the fact that MAPCs only survived for 7 days in the limb according to in vivo optical imaging of luciferase-transfected MAPCs.

"The results add to the growing body of science indicating that stem cells promote flow recovery more from their paracrine effects on host cells than from their engraftment into new blood vessels," said Dr. Lindner. "These are the first data to show that these stem cells act to promote vascular remodeling by migrating to a perivascular location where they rebalance the immune response toward a more regenerative phenotype involving pro-angiogenic monocytes."

Dr. Lindner said, "both endothelial activation and chemokine signaling of migration are operative in this process and these responses are sustained beyond MAPC lifespan likely because of the self-sustaining nature of the monocyte immune response." The future directions of his team's research will be: (1) to determine the specific biochemical signals by which MAPCs exert their paracrine effects, (2) to evaluate whether the paracrine effects can be modified by the MAPC growth environment, and (3) to test whether these same effects take place in humans with severe peripheral artery disease.

The Lindner team reported their findings in a paper titled, Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia, which was published in the journal Circulation.


Jae Choon Ryu (1); Brian P. Davidson (1); Aris Xie (1); Yue Qi (1); Daogang Zha (1); J. Todd Belcik (1); Evan S. Caplan (1); Juliana M. Woda (2); Catherine C. Hedrick (3); Richard N. Hanna (3); Nicholas Lehman (2); Yan Zhao (1); Anthony Ting (2); Jonathan R. Lindner (4*)

1Oregon Health & Science University, Portland, OR
2Athersys, Inc., Cleveland, OH
3La Jolla Institute for Allergy and Immunology, La Jolla, CA
4Oregon Health & Science University, Portland, OR
* Cardiovascular Division, Oregon Health & Science University

About the Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.

More Published Papers

The entire list of OHSU papers published this month is here.