Developing Measures of Safety and Efficacy for Tissue-engineered Products

Principal Investigator: Brenton McCright, PhD
Office / Division / Lab: OCTGT / DCGT / CTTB

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Overview

Public Health Issue: The primary purpose of cell and tissue engineering is to address the growing need for tissues and organs required to treat patients with degenerative diseases. To avoid treating patients with poorly engineered, uncharacterized collections of transplanted cells that will not function reliably and may damage other organ systems in a patient, the FDA is developing methods for predictable characterization of these products, and for evaluating the safety and efficacy of these novel cell-based therapies.

Regulatory Contribution: These methods require that we understand the key processes that determine how cells mature and contribute to the formation of organs and tissues. Identification of these key biological factors controlling the growth and development of organs and tissues will help the FDA predict the behavior of cell populations or tissue-engineered products administered to patients, and to devise quality control tests for such products in order to predict safety and efficacy.

Research Approach: The goal of this research program is to evaluate how cells mature and contribute to the formation of organs and tissues. We study tissue maturation and cell fate determination in the mouse because mouse organ development is nearly identical to human organogenesis. Molecular signals between cells determine whether a cell remains in a replicating immature state or stops dividing and matures. One such molecular signal important in development of most organs is the Notch pathway using our transgenic mice in which this molecule can be turned on or off in response to certain stimuli. This allows us to study when and where Notch must be expressed for normal organ development.

Mission Relevance and Outcomes: Results from our studies will indicate when and where key biological signals are be expressed in certain tissues or organs. The information will provide markers that can be used in product testing and methods for evaluating the safety and efficacy of tissue engineered and cell therapy products.

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Publications

Dev Dyn 2008 Apr;237(4):1144-52
Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells.
Varadkar P, Kraman M, Despres D, Ma G, Lozier J, McCright B

PLoS ONE 2008 Mar 26;3(3):e1851
Notch signaling regulates bile duct morphogenesis in mice.
Lozier J, McCright B, Gridley T

Immunity 2007 Jul;27(1):89-99
Direct regulation of gata3 expression determines the T helper differentiation potential of notch.
Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, Busslinger M, McCright B, Gridley T, Flavell RA

Genesis 2006 Jan;44(1):29-33
Generation of new Notch2 mutant alleles.
McCright B, Lozier J, Gridley T

FASEB J 2005 Aug;19(10):1311-3
Functional conservation of Notch1 and Notch2 intracellular domains.
Kraman M, McCright B