Novel therapeutics using mesenchymal stem cells for treatment

The Center for Stem Cell Research and Regenerative Medicine performs research using mesenchymal stem/stromal cells for treatment via cell therapies and  tissue engineering strategies.

Adult stem cells have long been investigated as therapeutic entities due to their inherent dynamic abilities to respond to local tissue environment and to restore homeostasis in the body.

Mesenchymal stem/stromal cells (MSCs) are categorised as adult stem cells and have been isolated from numerous tissue sources, including bone marrow, umbilical cord blood and adipose tissue. MSCs located in adipose tissue are denoted as adipose-derived stem cells (ASCs).

ASCs have similar properties and therapeutic effects as the more widely-investigated MSCs from the bone marrow. However, ASCs offer several distinct advantages. ASCs are harvested by less invasive procedures; they are found in higher frequencies regarding stem cells per gram of tissue and they can also be culture expanded to high numbers and cryopreserved for later use.

ASCs have been the focus of much attention due to their multilineage differentiation potential, regenerative properties and immunomodulatory effects. ASCs efficiently differentiate into mesodermal lineage cells, such as adipogenic, osteogenic, chondrogenic, and myogenic lineages. ASCs may also be immune privileged as a result of an absence of the expression of MHC class II molecules and costimulatory molecules, which may make them effective for allogeneic treatment strategies.

The centre for Stem Cell Research and Regenerative Medicine (CSCRRM) at the Tulane University School of Medicine in New Orleans, Louisiana has an intense research focus on the use of MSCs as therapeutic entities for the treatment of disease or injury via cell therapies or tissue engineering strategies.

The centre has a highly collaborative research program composed of faculty members from across Tulane University from diverse departments including Pharmacology, Surgery, Physiology, Urology, Plastic Surgery, Otolaryngology, Orthopaedics, Biomedical Engineering, and Chemical and Biomolecular Engineering. The CSCRRM was established in July of 2000 and the primary goal of the centre is to develop new therapies for a series of common diseases that including stroke, bone defects, wound healing, multiple sclerosis, osteoporosis, and traumatic brain injury. A significant research effort is devoted to understanding the biologic and therapeutic properties of MSCs. It is anticipated that in the coming year, the centre will undertake clinical trials testing autologous MSCs for osteoarthritis, traumatic brain injury and multiple sclerosis.

The research performed at the centre and across the globe suggests that ASCs may be highly effective for the treatment of multiple disease states. To that end, the centre has developed a broad research program focused on pre-clinical and clinical research
using ASCs.

The centre has techniques for the isolation of ASCs from various sources of adipose tissue from rodents, nonhuman primates and human tissue samples. Adipose tissue is broken down via treatment with collagenase and physical disruption to isolate the stromal vascular fraction (SVF), a heterogeneous population of cells composed of ASCs (approximately 15-30% of the total cell population), endothelial cells (10-20%), pericytes (3-5%), and immune cells (25-45%).

EAE Model

The potent immunomodulatory properties of ASCs suggests they may be therapeutic for autoimmune diseases, which are primarily driven by immune cell activity. The centre has investigated ASCs as a treatment for Multiple Sclerosis in the pre-clinical Experimental Autoimmune Encephalomyelitis (EAE) mouse model. Hallmarks of MS include demyelination, inflammation, and white matter lesions in the CNS, which are recapitulated in the EAE model.

Our investigations have focused on infusions of ASCs or BMSCs isolated from syngeneic mice and humans via the intraperitoneal or intravenous routes. Our data collected to date demonstrates a therapeutic benefit of ASC infusions whether they are delivered in the early, middle or late stage disease, as indicated by improved neuromotor functions and reduced demyelination. Our team has also reported that the ASCs directly influence immune cell frequency and activity in vivo.

Bone Regeneration Models

Bones possess robust regenerative capacity allowing animals to repair fractures in a rapid and efficient manner. However, when the defect becomes a critical size bone does not effectively repair or regenerate. Critical-sized bone defects in humans can be a consequence of severe trauma, blast injuries, or bone resection on a large scale due to infection or tumours. Researchers at the Center have been investigating whether ASCs can enhance bone regeneration in critical size defects using two critical-size defect models.

Segmental defect model

Orthopedic repair of critical-sized defects generally requires an invasive procedure that may include autologous or allogeneic bone grafting. The centre uses a femoral defect model in which a 3mm length of bone is surgically resected and stabilised with a pre-fabricated stainless-steel medullary pin inserted between two ends of the bone. The centre have used this model to investigate the effectiveness of novel scaffolds alone or in conjugation with stem cells including BMSCs and ASCs. The centre has the ability to monitor bone regeneration by micro-CT and post-necropsy by IVIS, assays for quality of the bone and histologic analyses.

Cranial defect model

The centre also uses a cranial defect model in mice to investigate stem cells and scaffolds for bone regeneration. The critical size, 4mm, calvarial defects are created in the right parietal bone of adult male mice. A unilateral full thickness defect is created using diamond-coated trephine bits in the non-suture-associated portion of the bone. Defects can then be filled with various scaffold materials or scaffolds unfused with stem cells to assess their ability to regenerate bone. Again, healing of the defects can be followed over time suing micro-CT and or histologic analyses.

Pressure ulcer model

As humans live longer, the number of people at risk for the development of pressure ulcers will increase considerably. It has been estimated that nearly 20% of nursing home residents will develop pressure ulcers, and the costs of treating these wounds are a sizable portion of the health care budget. It has been demonstrated that repeated cycles of ischemia and reperfusion induced by exposure of mouse skin to magnets induces a wound that closely mimics human pressure ulcers. When the pressure ulcer wounds are treated with ASCs, a dose-dependent and significant acceleration in wound closure rates and improved tissue histology are observed. These studies demonstrate the utility of this pre-clinical model for the evaluation of novel tissue engineering and regenerative medical approaches to treat pressure ulcers in humans.

Large Animal Models

The use of large animal models may be an essential step in the preclinical assessment of novel regenerative medicine therapeutics. The CSCRRM operates a research program at the Tulane National Primate Research Center (TNPRC), which is part of Tulane University.

The TNPRC one of seven NIH-funded National Primate Research Centers with the shared mission of finding causes, preventions, treatments, and cures for infectious diseases and chronic conditions that affect the lives of people and animals worldwide.

The TNPRC uses nonhuman primates as biomedical research models. The TNPRC has significant expertise in models of infectious diseases including HIV treatment (testing pharmacologic and genetic strategies) and prevention, Lyme disease, tuberculosis, and zika virus. The CSCRRM has independent research efforts and has partnered with academic, pharmaceutical and biotechnology companies on collaborative research projects focused on assessing the safety, toxicity and efficacy of novel interventions based on gene therapies, stem cells and tissue engineered products. The centre have focused on naïve animals for the safety and toxicity testing and have analysed biologic scaffolds, gene therapy products and stem cells in vivo.

The CSCRRM develops novel technologies for regenerative medicine with an emphasis on commercial developments. The centre has a meaningful patent profile on novel discoveries made by faculty. The centre has an extensive history of executing research collaborations with both academic (more than 125 collaborations) and biotechnology partners (20 collaborations). The centre can act as a contract research organisation and perform specific studies as designed by our collaborators. Tbe research group can also serve as a full scientific partner and be directly involved with the design, execution and analysis of studies that were collaboratively developed.

To explore collaborative or contract research projects, please reach out to Professor Bruce Bunnell.

Professor Bruce A Bunnell, PhD
Center for Stem Cell Research and Regenerative Medicine
Tulane University School of Medicine
+1 504 988 3329

Please note, this article will feature in the March 2020 issue of our publication.

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