Lorin Olson, Ph.D.
Cardiovascular Biology Research Program
Lab website: http://olson.omrf.org/
Our bodies have the capacity to repair themselves through an intricate process that closes the wound and returns the damaged tissue to a functional state. This complex process works remarkably well when we are young, but it is prone to interruption as we age. Non-healing chronic wounds commonly occur in the elderly and those who have poor circulation due to diabetes or immobility. The opposite of a chronic wound is scar tissue, which occurs when overactive repair processes create excessive new tissue. This is known as fibrosis, and it can attack any organ where local stress is not controlled. This occurs, for example, in our blood vessels when high cholesterol stresses the circulation and creates a build-up of scar tissue (called atherosclerosis) that ultimately causes most heart attacks and strokes. There is a tremendous need for new technology to solve the medical problems of non-healing wounds and fibrosis, and this can only come through a better understanding of the wound repair process.
Injured or stressed tissues produce a small protein signal called platelet-derived growth factor (PDGF). Some cells have specific PDGF-receptors located on the cell surface that allow them to sense PDGF in the wound environment. More than 30 years ago it was discovered that PDGF stimulates wound repair. But too much PDGF promotes fibrosis. Therefore, our bodies must maintain a careful balance of PDGF in order to achieve proper tissue repair.
A few cells in the body, called adult stem cells, have great potential to regenerate damaged tissue and influence neighboring cells to support wound repair. Some kinds of adult stem cells, called mesenchymal stem cells (MSCs), have PDGF-receptors. It is not known why MSCs have PDGF-receptors or if they are important in the overall wound-repair process. We hypothesize that MSCs may hold the key to optimal tissue repair via their response to PDGF in the wound environment.
The studies in my laboratory are designed to understand how PDGF works in wound repair and how too much PDGF leads to scar tissue. The wound repair process appears to be similar in mice and humans. Therefore, we study genetically engineered mice with different amounts of PDGF to understand how PDGF might be acting in human wound repair. We use different methods to remove MSCs from mice and study cell behavior in isolation. We can also mark these cells while they are still in the tissue and track their behavior during wound repair. Finally, we can transplant MSCs between healthy and injured tissue to determine how different amounts of PDGF can alter MSC behavior and potentially improve wound repair and avoid fibrosis. By understanding how wound repair is regulated by PDGF and MSCs, we hope to devise new therapies to close chronic wounds and limit or reverse fibrosis.
B.S., Brigham Young University, UT, 1996
Ph.D., University of California, San Diego, CA, 2004
Postdoc, Fred Hutchinson Cancer Research Center, Seattle, WA, 2005-2008
Postdoc, Mt. Sinai School of Medicine, New York City, NY, 2008-2010
Honors and Awards
1998 Digestive Disease Week Student Abstract Award
2007-2009 American Cancer Society Postdoctoral Fellowship
2010 Best Publication in 2009 Award, Mt. Sinai School of Medicine Office of Postdoctoral Affairs
Joined OMRF Scientific Staff in 2010
My laboratory studies how the platelet-derived growth factor (PDGF) signaling pathway is utilized in adult tissues and how it contributes to conditions like fibrosis. We have generated conditional knockin mice with mutations in the two PDGF receptors (PDGFRa and PDGFRb), which render the receptors constitutively active and ligand independent. Using tissue-specific and tamoxifen-inducible Cre-lox strategies, we can now activate the PDGF signaling pathway in a variety of cell types and experimental conditions. In addition, we use lineage tracing, flow cytometry, microarrays, and stem cell assays to determine the underlying mechanisms of PDGF signaling in normal biology and disease processes.
Skin fibrosis and wound repair: Fibrosis is a process associated with chronic inflammation where collagen produced by activated myofibroblasts permanently scars tissues and leads to organ dysfunction. Every organ system can be damaged by fibrosis, which contributes to diseases such as autoimmunity and atherosclerosis. It is well known that inflammatory cells secrete PDGF, but its role in fibrosis has been unclear. We have recently demonstrated that constitutive PDGFRa signaling is sufficient to cause fibrosis in the skin and many other organs (Olson & Soriano 2009). Going forward, we are using a skin-injury model to systematically investigate how PDGFRa signaling alters the wound-repair process to create scar tissue. There is significant controversy about the origin of fibroblasts and myofibroblasts that produce extracellular matrix during fibrosis. We hypothesize that PDGFRa signaling drives fibrosis by 1) cell-autonomously directing the balance of progenitor cell differentiation towards a fibroblast/myofibroblast fate or 2) inducing secondary signals that act in a paracrine fashion to regulate fibroblast/myofibroblast biology. We are developing new mouse models to lineage trace clones of PDGFRa-mutant cells with a fluorescent reporter. This approach will allow us to track the fates of PDGFRa-mutant cells during fibrosis or wound repair. It will also be useful for isolating cells at any stage of disease for detailed characterization of cell surface markers and gene expression.
Vascular fibrosis and atherosclerosis: Advanced atherosclerotic lesions cause the majority of heart attacks and strokes in humans, but these types of lesions do not occur in experimental animals. This creates severe limitations in understanding the development of advanced lesions and the mechanisms of plaque rupture. PDGF is an important mitogen for smooth muscle cells (SMCs) and is thought to recruit SMCs out of the vessel wall to drive neointimal fibrosis and atherosclerosis. We have recently demonstrated that adipocyte and vascular smooth muscle cell differentiation are inhibited by constitutive PDGFRb signaling (Olson & Soriano 2011). We are building on these findings to develop a mouse model for SMC-specific activation of PDGFRb, which will allow us to investigate SMC dedifferentiation, recruitment, and proinflammatory signaling during atherosclerosis. Our preliminary studies suggest that this approach leads to advanced atherosclerotic lesions throughout the arterial tree, creating a lethal atherosclerosis burden in mutant mice. We expect this new mouse model to allow us to investigate the critical question of how SMCs in the vessel wall are transformed into neointimal myofibroblasts in advanced stages of disease.
* He C, Medley SC, Hu T, Hinsdale ME, Lupu F, Virmani R, Olson LE. PDGFRbeta signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nat Commun 6:7770, 2015. [Abstract]
* Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D, Wren JD, Olson LE. PDGFRalpha signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev 2015. [Abstract] EPub
Iwayama T, Olson LE. Involvement of PDGF in Fibrosis and Scleroderma: Recent Insights from Animal Models and Potential Therapeutic Opportunities. Curr Rheumatol Rep 15:304, 2013. [Abstract]
Olson LE, Soriano P. PDGFRbeta signaling regulates mural cell plasticity and inhibits fat development. Dev Cell 20:815-826, 2011. [Abstract]
Olson LE, Soriano P. Increased PDGFRα activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16:303-313, 2009. Abstract
Olson LE, Tollkuhn J, Scafoglio C, Krones A, Zhang J, Ohgi KA, Wu W, Taketo MM, Kemler R, Grosschedl R, Rose D, Li X, Rosenfeld MG. Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination. Cell 125:593-605, 2006. Abstract
Olson LE, Zhang J, Taylor H, Rose DW, Rosenfeld MG. Barx2 functions through distinct corepressor classes to regulate hair follicle remodeling. Proc Natl Acad Sci USA 102:3708-3713, 2005. Abstract
Toyo-Oka K, Hirotsune S, Gambello MJ, Zhou ZQ, Olson L, Rosenfeld MG, Eisenman R, Hurlin P, Wynshaw-Boris A. Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome. Hum Mol Genet 13:1057-1067, 2004. Abstract
Olson LE, Rosenfeld MG. Perspective: genetic and genomic approaches in elucidating mechanisms of pituitary development. Endocrinology 143:2007-2011, 2002. Abstract
Cardiovascular Biology Research Program, MS 45
Oklahoma Medical Research Foundation
825 NE 13th Street, Oklahoma City, OK 73104
Phone: (405) 271-7535; (405) 271-7390
Fax: (405) 271-7417