The Role of Platelet-Derived Growth Factor in the Migration of Human Adipose-Derived Mesenchymal Stem Cells

Candice A. Shaifer, PhD
Postdoctoral Fellow

Introduction:


Each year 40,000 people are diagnosed with primary brain tumors, the majority of which are glioblastoma (GB). Glioblastoma is the most common brain tumor in adults and is the most malignant subtype. Despite best treatments with maximum surgical resection, radiation and chemotherapy, long-term survival of GB patients is rare (median survival is 14.6 months). Complete surgical resection is a challenge due to the diffusely infiltrative growth pattern of GB, and systemic therapy is limited by the selectivity of the blood brain barrier (BBB). According to the World Health Organization, astrocytomas are classified as either localized or diffuse based on how they interact with their immediate microenvironment. Localized GB exhibit limited invasiveness and a restricted pattern of growth. On the other hand, diffuse GB is invasive at the peritumoral edge and is able to metastasize to distant sites. The success of current therapies has been met with limitations due to the disseminated nature of these tumors. The use of mesenchymal stem cells (MSC) has become an attractive option. Mesenchymal stem cells (MSCs) are adult stem cells traditionally found in the bone marrow. However, MSCs can be obtained from fat (adipose) tissue, umbilical cord blood, peripheral blood, fallopian tube, and fetal liver and lung. These cells are also multipotent and can differentiate into various mesenchymal lineage cells including adipocytes (fat), osteocytes (bone), and chondrocytes (cartilage), muscle and skin.


MSCs derived from fat tissue, known as adipose-derived mesenchymal stem cells (hAMSCs), are attractive for clinical use because they possess a natural affinity for tumors, can be easily isolated from fat tissue, grow well to expand to the numbers required for application, and can be genetically modified through various methods. Thus, MSCs have enormous therapeutic potential for brain tumor therapy. Platelet-derived growth factor (PDGF) and its receptor PDGF-R are over expressed in gliomas. PDGF is a strong inducer of cell migration and therefore targeting this molecule could potentially enhance the migration of therapeutic hAMSCs towards gliomas.


Aims/Goals:


1.To determine whether human hAMSCs are able to migrate to the smaller nest of glioma cells that remain after surgical resection.
2.To determine if the PDGF-BB/PDGFR-BB signaling pathway is cue that mediates stem cell migration in vitro.
3.To determine whether PDGF-BB signaling mediates hAMSC migration towards gliomas in vivo.


Clinical Implications/Relate to Patients:


As scientist our future goal would be to use hAMSCs in the treatment of glioblastoma. For example, an individual patient would donate their fat tissue and we would bring the tissue back to the laboratory to be expanded ex vivo (outside of the body and in the laboratory) by our team. Subsequently, the patient’s MSCs would be altered to express the therapeutic gene of interest, expanded once more and then administered back into the patient to selectively target and destroy their brain tumor cells.