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  1. Biologics Research Projects

Developing Ways to Measure Safety and Efficacy for Tissue-engineered Products

Brenton McCright headshot

Brenton McCright, Ph.D.

Office of Tissues and Advanced Therapies
Division of Cellular and Gene Therapies
Cellular and Tissue Therapy Branch

[email protected]

Biosketch

Dr. McCright received his BS degree in electrical engineering from the University of Maryland and worked for a number of years in signal analysis and computer system design. He received his Ph.D. degree in Oncological Sciences from the University of Utah in 1997. The focus of his thesis was the identification and characterization of novel PP2A regulatory subunits involved in controlling cell proliferation. Dr. McCright then studied developmental biology and mammalian genetics during a post-doctoral fellowship research at The Jackson Laboratory.

He joined the Division of Cellular and Gene Therapies, in the Office of Cellular, Tissue, and Gene Therapies, at the Center for Biologics Evaluation and Research of the FDA as a Senior Staff Fellow in 2002 and became a Senior Investigator in the Cellular Therapy and Tissues Branch in 2009.

Dr. McCright’s lab investigates the function of key signaling molecules during organogenesis and tissue repair using a variety of in vivo imaging tools, including magnetic resonance imaging (MRI).  The goal is to identify molecules that may help to predict the effectiveness of cellular therapies. He is currently studying spindle assembly checkpoint control by PP2A-B56gamma and identifying neural stem cell “stemness” factors. Dr. McCright also reviews INDs and works on policy development for cellular therapies.

General Overview

The primary purpose of cell and tissue engineering is to fulfill the growing need for new therapies required to treat patients with degenerative diseases. Collections of transplanted cells that are poorly engineered and uncharacterized (i.e., cells whose biological characteristics are not fully identified) may not function reliably in the body after being transplanted. Moreover, such cells might even damage other organ systems of the patient receiving them, or form tumors. Therefore, our laboratory studies the key processes that determine how cells mature and contribute to the formation of organs and tissues. We perform our studies in transgenic mouse models and in human stem cells.
We believe that understanding the evolutionarily conserved signaling pathways involved in the regulation of mammalian organ development and stem cell differentiation is critical to successful cell therapy, since these factors are also required for tissue repair and regeneration.

The goal of our work is to identify and understand the molecular signals that will help us to predict how a cell will function after being administered to patients. We are especially interested in understanding the molecular signals that determine whether a cell remains immature and continues to multiply, or stops dividing and matures into a cell that performs a specific function in the body.

The molecular signals we study are evolutionarily conserved (present in all animals) and widely used (present in many cell types). We developed genetically engineered mice in which these molecules can be turned on or off in response to certain stimuli. This allows us to study when these signals are needed during tissue repair and organ development. Because organ development in mice is very similar to that of humans, our laboratory uses the mouse as a model to study how tissues mature and how biological signals determine the fate of cells in the body.

In addition to studying the function of key pathways of biochemical signaling that guide the development of organs, we analyze the function of these pathways in progenitor cells, such as those used for cellular therapies. Regarding their potential to form new tissues, progenitor cells are at a developmental state between embryonic stem cells and mature, functional, specific cells. Since progenitors are more mature than embryonic stem cells, they are limited in the type(s) of cells they can become.

Identifying biological factors controlling growth and development of organs and tissues provides data FDA can use to advise sponsors how to characterize cell populations or tissue-engineered products administered to patients. Our studies provided tools needed to evaluate potential cell sources and techniques for growing cells, and to identify markers that predict how cells will behave. It will also help agency scientists develop new approaches for quality assessment of novel cell-based therapies that are better able to predict safety and efficacy than are standard methods used for conventional therapies and biologics.

Scientific Overview

Our research is focused on elucidating the function of key cell-fate-determining factors that we can use to evaluate the safety and efficacy of cellular therapies and tissue engineered products. The research focuses on evaluating requirements for specific molecules during mouse embryonic organ development and in human models of cellular therapies. Because successful repair and regeneration of damaged tissue will require the same signaling pathways used for embryonic organ formation, we expect findings from these two approaches to complement each other.

Regulation of Protein Phosphatase 2A (PP2A) during development and progenitor cell proliferation

We are phenotypically analyzing mice in which the B56 regulatory subunits of PP2A have been inactivated. Our findings demonstrate that misregulation of this conserved signaling pathway disrupts the normal expansion and differentiation of cardiac progenitor cells. This suggests that it might be useful to monitor the expression of these molecules when evaluating the developmental status of cardiac progenitor cells used in therapies.

The regulation of PP2A activity has also been shown to be critical in the inhibition of cell transformation. In cells derived from mice that have PP2A-B56 regulatory subunits inactivated, we found that cells do not arrest in mitosis when treated with cell cycling inhibitors. The spindle assembly checkpoint (SAC) is used by proliferating cells to ensure the integrity of chromosome distribution, and it is an important mechanism used by cells to control tumorigenesis. The mechanism behind the bypass of the SAC is being further investigated by extending our studies into human induced pluripotent stem cells (hiPSCs), a cell type that is used for cellular therapies. PP2A-B56 regulatory subunits will be overexpressed and inhibited in hiPSCs to evaluate their role in controlling genomic stability and cellular differentiation.

Characterization of Neural Stem Cells (NSCs) based on cell morphology and developmental markers:  

NSCs isolated from tissues and pluripotent cells are being developed as cellular therapies aimed at treating neurodegenerative diseases. During NSC culture and expansion it is important the cells do not differentiate prematurely, since this may have an unfavorable effect on product quality and yield. Using expression of NSC developmental markers as a reference, we will use flow cytometry to identify a specific morphological profile for undifferentiated murine and human NSCs. These studies will identify new methods to evaluate the differentiation status of NSCs grown in culture for use in cellular therapies.

After transplantation of cellular therapy products, it is often unclear how long the cells survive and if they migrate away from the injection site. Therefore, magnetic resonance imaging (MRI) contrast agents including superparamagnetic iron oxide nanoparticles (SPIONs) and perfluorocarbons (PFCs) are being used or proposed for tracking cellular therapies in clinical trials. We will use MRI to compare the survival and migration of NSCs transplanted into mice. We will use NSC populations with variable amounts of undifferentiated cells as determined by expression of the GFP reporter constructs. The goal is to determine if MRI can be used to detect differences in cellular behavior post-transplantation.  MRI technologies that improve imaging will also be developed.

Publications

  1. MAGMA 2020 Oct;33(5):725-33
    Sensitivity and uniformity improvement of phased array MR images using inductive coupling and RF detuning circuits.
    Park BS, Rajan SS, McCright B

  2. MAGMA 2019 Feb;32(1):15-23 Improvement of 19F MR image uniformity in a mouse model of cellular therapy using inductive coupling.
    Park BS, Ma G, Koch WT, Rajan SS, Mastromanolis M, Lam J, Sung K, McCright B

  3. Cytotherapy 2018 Dec;20(12):1472-85
    Evaluation of the differentiation status of neural stem cells based on cell morphology and the expression of Notch and Sox2.
    Ma G, Abbasi F, Koch WT, Mostowski H, Varadkar P, Mccright B

  4. J Vis Exp 2018 Mar 14;(133):e57389
    Live cell imaging of chromosome segregation during mitosis.
    Varadkar P, Takeda K, McCright B

  5. IEEE Trans Electromagn Compat 2017 Oct;59(5):1382-9
    Improvement of electromagnetic field distributions using high dielectric constant (HDC) materials for CTL-spine MRI: numerical simulations and experiments.
    Park BS, McCright B, Angelone LM, Razjouyan A, Rajan SS

  6. IEEE Trans Electromagn Compat 2017 Oct;59(5):1390-9
    RF safety evaluation of a breast tissue expander device for MRI: numerical simulation and experiment.
    Park BS, Razjouyan A, Angelone LM, McCright B, Rajan SS

  7. Cell Cycle 2017 Jun 18;16(12):1210-9
    PP2A-B56gamma is required for an efficient spindle assembly checkpoint.
    Varadkar P, Abbasi F, Takeda K, Dyson JJ, McCright B

 

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