Fibrin matrices enhance the transplant and efficacy of cytotoxic stem cell therapy for post-surgical cancer

Abstract

Tumor-homing cytotoxic stem cell (SC) therapy is a promising new approach for treating the incurable brain cancer glioblastoma (GBM). However, problems of retaining cytotoxic SCs within the post-surgical GBM resection cavity are likely to significantly limit the clinical utility of this strategy. Here, we describe a new fibrin-based transplant approach capable of increasing cytotoxic SC retention and persistence within the resection cavity, yet remaining permissive to tumoritropic migration. This fibrin-based transplant can effectively treat both solid and post-surgical human GBM in mice. Using our murine model of image-guided model of GBM resection, we discovered that suspending human mesenchymal stem cells (hMSCS) in a fibrin matrix increased initial retention in the surgical resection cavity 2-fold and prolonged persistence in the cavity 3-fold compared to conventional delivery strategies. Time-lapse motion analysis revealed that cytotoxic hMSCs in the fibrin matrix remain tumoritropic, rapidly migrating from the fibrin matrix to co-localize with cultured human GBM cells. We encapsulated hMSCs releasing the cytotoxic agent TRAIL (hMSC-sTR) in fibrin, and found hMSC-sTR/fibrin therapy reduced the viability of multiple 3-D human GBM spheroids and regressed established human GBM xenografts 3-fold in 11 days. Mimicking clinical therapy of surgically resected GBM, intra-cavity seeding of therapeutic hMSC-sTR encapsulated in fibrin reduced post-surgical GBM volumes 6-fold, increased time to recurrence 4-fold, and prolonged median survival from 15 to 36 days compared to control-treated animals. Fibrin-based SC therapy could represent a clinically compatible, viable treatment to suppress recurrence of post-surgical GBM and other lethal cancer types.

Electrospun nanofibrous scaffolds increase the efficacy of stem cell-mediated therapy of surgically resected glioblastoma

“…In contrast to previous studies using hydrogel, the minimal cross-sectional thickness of bENS is advantageous because it should minimize the risk of mass effect and associated morbidity and mortality that cavity-filling strategies could cause if the surgical cavity of human patients is filled with polymer/stem cell mixtures. Unlike previous strategies [8,26], bENS delivers therapeutic hMSCs seeded on the surface of the scaffold rather than encapsulated. This raises the potential to explore new parameters in scaffold architecture, topography, and composition as we work towards defining the optimal scaffold properties for stem cell-based GBM therapy.…”

Tissue engineering scaffolds in the treatment of brain disorders in geriatric patients

“…In comparison to non‐scaffold‐mediated hMSC transplant, the hMSC‐loaded fibrin had a twofold and threefold cell retention and long‐term persistence, respectively. In addition, the scaffold transplant resulted in a six‐fold post‐surgical GBM volume reduction and prolonged median survival compared to control . Earlier and later studies by members of the same research group using different scaffolds have yielded identical results.…”

“…Of interest to this work is the use of tissue engineering scaffolds for brain cavity reconstruction after surgery (Figure ). A group of researchers have extensively studied the prospect of cell‐mediated therapy using cytotoxic tumor cells . The group fabricated a fibrin scaffold and seeded it with hMSCs which was later transplanted in a mice brain tumor cavity.…”

Gold Nanowires/Fibrin Nanostructure as Microfluidics Platforms for Enhancing Stem Cell Differentiation: Bio-AFM Study

“…One particularly interesting natural polymer is fibrin. Fibrin is characterized by low cytotoxicity, excellent biocompatibility, enhanced cell adhesion, and cell-mediated degradation kinetics [6,17]. However, poor knowledge of the mechanical properties of fibrin, constitute one of the most important limitations of this natural biomaterial [6].…”

“…Overall, human mesenchymal cells are highly susceptible to the physico-chemical cues of their surrounding ECM. This makes the cells good candidates for further study [7,[15][16][17]. Therefore, the key to defining a stem cell's fate involves investigating the effects of biophysical parameters such as stiffness, topography, and the role of nanomaterials incorporation on stem cell differentiation.…”