Download Journal of Virology

Engineered MSCs as Novel Therapeutics
for Intractable Diseases
Young Chul Sung (POSTECH)
Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating into a variety of
cell types, implying that MSCs are the attractive therapeutics in regenerative medicine and tissue
engineering. In addition, immunosuppressive effects of MSCs by secreting soluble mediators have been
used for therapy of graft-versus-host disease and various autoimmune diseases in the clinical setting as well
as animal experiments. Recently, MSCs were known to have tropism to inflammatory sites, including
damaged tissues and tumors, suggesting the targeted cancer gene therapy could be possible using
genetically engineered MSCs to express antitumor molecules. Despite of these promises, MSCs by
themselves have exhibited the limited efficacy and specific differentiation to the desired cell type. In
addition, safety concerns such as possible risk of ectopic tissue formation, systemic immune suppression,
and malignant transformation remain unsolved. In these regards, engineered MSCs generated by ex vivo
genetic modification could be the second generation stem cell medicine with high potency and safety.
Unfortunately, MSCs lack coxsackievirus and adenovirus receptor (CAR), a primary receptor of
recombinant adenovirus (rAd) which is one of the most potent gene delivery vectors.
Although
cell-
permeable peptides (CPPs), small basic peptides composed of less than 20 amino acids, promote the
transduction of MSCs by rAd, high concentration (more than 0.5 mM) of CPP is required to increase
transduction efficiency by approximately 10 folds. Interestingly, more than 95% transduction efficiencies
were achieved using branched tetrameric CPPs (tCPPs) at 3000–5000-fold less than that of monomeric
CPPs. In a critical-size calvarial defect model, the inclusion of tCPPs in ex vivo transduction of rAd
expressing bone morphogenetic protein 2 (BMP2) into MSCs promoted highly mineralized bone formation.
In addition, MSCs that were transduced with rAd expressing brain-derived neurotrophic factor (BDNF)
improved functional recovery in a spinal cord injury model.
Use of engineered MSCs are also promising strategy for cancer gene therapy. In intracranial glioma model,
engineered MSCs expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) retained
tumor-specific migration ability, regressed tumor mass, and prolonged survival of glioma-bearing mice. In
addition, engineered MSCs expressing both TRAIL and herpes simplex virus thymidine kinase (HSV-TK)
showed synergistic antitumor effects on pulmonary metastasis of renal cancer. In immunocompetent mice,
intratumoral injection of engineered MSCs expressing modified interleukin-12 (MSC/IL-12M) significantly
inhibited tumor growth and completely protected intracranial glioma in 70% of the treated mice, which is
correlated with increased T cell infiltration and antiangiogenesis. In mouse melanoma model, intratumoral
injection of MSC/IL-12M elicited stronger antitumor effect than rAd expressing IL-12M by inducing
prolonged and higher IL-12 level, which is further enhanced by using cell carrier.
. These results demonstrated the potential for engineered MSCs as novel therapeutics to overcome low
efficacy and safety problems of conventional therapies for intractable diseases such as tissue injuries,
autoimmune diseases, and cancers.