Smith C, Chaichana K, Lee Y, Lin B, Stanko KM, O’Donnell T, Gupta S, Shah SR, Wang J, Wuesekera O, Delannoy M, Levchenko A, Quinones-Hinojosa A. Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer. Stem Cells Transl Med 4:239-251, 2015.

Prepared by: Guy Giubilato and Sudharani Jujuru, Graduate Course in Stem Cell, Fall 2015

LAYMAN’S SUMMARY

Mesenchymal stem cells (MSCs) are multipotent stem cells that can be found in several tissues such as bone marrow and adipose tissue. There is a growing interest to use MSCs for therapeutic delivery of drugs to treat neurological disorders. The attractiveness of using MSCs for such treatment are mostly due to the following: MSCs can home to sites of tissue injury; can cross the blood-brain barrier to sites of neurological, and do not provoke an immune response. In addition, unlike embryonic stem cells, MSCs are adult-derived, indicating reduced ethical concerns and ease in harvesting the source tissues. Unfortunately, MSCs have shown low therapeutic efficiency in treating neurological conditions because of their low numbers of engraftment (<1%) and their tendency to target healthy tissue rather than damaged tissue, resulting in unwanted side effects. Thus, the authors of the paper studied method to increase the therapeutic efficacy of MSCs on neurological disorders. The authors demonstrated that growth of human adipose-derived MSCs (hAMSCs), in the presence of key signaling proteins involved in MSC homing, enhanced the ability to home and integrate to sites of brain cancer. The addition of homing factors to the media provided the designation, “prime MSCs”. This treatment enhanced cell adhesion, blood-brain barrier migration, and homing speed, with accuracy to the diseased tissues across the blood-brain barrier. The homing of MSCs did not affect their ability to differentiate. The research demonstrated that hAMSCs can be used as cellular vehicle to deliver anti-cancer drugs. The ability to enhance stem cell homing, engraftment, and blood-brain barrier breaching, by pretreating them with media that mimic the microenvironment increased their homing to the brain. Since this study used brain tumor as a model, future research would need to study if similar pretreatment could be applied to deliver MSCs to treat other neurological disorders, such as stroke, Multiple Sclerosis, and Parkinson’s Disease.

SCIENTIFIC SUMMARY

Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into cells of all germ layers, e.g., osteoblasts, chondrocytes, adipocytes, myocytes and neurons. Recent research has shown that MSCs have the potential to be used as cellular vehicle to deliver treatments for neurological injury and cancers. First, MSCs “possess an intrinsic tropism” for neurological pathologies; second, MSCs “reside within the bloodstream as pericytes”, and thus are readily available to home to sites of injury; third, MSCs can bypass the blood-brain barrier, allowing them to aid in neurological regeneration, and fourth, MSCs are non-immunogenic, easy to harvest, adult stem cells, so they do not face the same ethical scrutiny as embryonic stem cells. Despite the major advantages of MSC-based neurotherapies, issues regarding the accuracy and efficiency of MSC homing has hindered their clinical viability. The discussed studies proposed that preincubation of MSCs in media that chemically mimics the local microenvironment of the pathogenic area would enhance the efficacy of MSC-mediated therapeutic delivery. Previous studies have shown that extracellular matrix (ECM) proteins facilitate communication between MSC receptors, such as platelet derived growth factor receptor (PDGFR-β) and MSC migration mechanisms that are controlled by the α5β1-integrin. More specifically, ECM proteins fibronectin (FN), which has demonstrated an ability to induce PDGFR-β signaling in an α5β1-integrin-dependent manner, and laminin (LM), which has been shown to increase PDGFR-β and increase MSC migration. Thus, the authors isolated human adipose-derived MSCs (hAMSCs) and preconditioned them using glioma-conditioned medium (GCM), FN, and LM in cell culture in order to test the effects of microenvironmental priming on hAMSC homing during in vitro and in vivo gliomal models. In vitro models to test the adhesion, transmigration, migration, and chemotaxis indicated improved homing ability. First, a single layer microfluidic device was constructed and coated with a monolayer of human brain microvascular endothelial cells (hBMECs) to test hAMSC adhesion to a stressed blood vessel environment. Next, a transmembrane chamber coated with an endothelial monolayer was constructed to study hAMSC transmigration across the blood-brain barrier. Then, hAMSCs were tested along an extracellular matrix structure to observe their migration and chemotactic movements in relation to a glioma microenvironment. GCM, FN, and LM were tested independently, as well as in a combination (primed MSCs). The results were consistent with independent treatments, as well as in the combined “prime” pretreatment. However, priming was shown to have the most dramatic enhancements on hAMSC adhesion, blood-brain barrier transmigration, ECM migration speed and alignment, hAMSC chemotactic response, and number of hAMSCs responding to the gliomal microenvironment in an in vitro model. Finally, the authors tested prime preconditioning in an in vivo murine gliomal model two weeks after injection and again found that preconditioning with GCM, FN, and LM show increased hAMSC adhesion, transmigration, migration, and chemotaxis. Preconditioned hAMSCs expressed commonly accepted MSC immunologic cell surface receptors, maintained normal MSC differentiation patterns, did not show an increase in growth rate, and did not affect glioblastomal cell growth; which overall demonstrated that preconditioning enhances the ability of MSCs to home to tumors, without altering their native identity or behavior. This research further implicates MSC as a potential therapeutic vehicle in neurologic damage or tumor states because of their trophic, paracrine, and immunomodulatory functions. Prime preconditioning shows promise as a method to enhance MSC homing and engraftment so as to make stem cell therapies more accessible. HAMSCs that are modified to secrete anti-cancer proteins, such as BMP-4, could serve as effective therapeutical treatments, or hAMSCs could be modified to deliver treatment against other neurological disorders, such as Parkinson’s Disease, Multiple Sclerosis, and stroke. The class found this paper to be insightful with the possibilities to advance the therapeutic capabilities of stem cells. However, this study is limited to glioma models, so studies regarding other disease states are necessary to prove preconditioning viability. Also, the authors did not monitor how long it took for the hAMSCs to reach the brain, and the retention time in the brain. Also, it was unclear what happened to the MSCs after they enter the diseased tissue. Long term in vivo studies would be necessary to analyze the fate of these hAMSCs once they have delivered treatment.

BIBLIOGRAPHY

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Salehi H,Amirpour N,Niapour A,Razavi S. An Overview of Neural Differentiation Potential of Human Adipose DerivedStemCells. Stem cell reviews and reports. 2015; 1-16