Two-photon Imaging as a Platform for the Real-time Evaluation of Human Glial Progenitor Cell Engraftment in the Lysosomal Storage Disorders

Lay Summary

Determining Whether Embryonic Cells Can Reverse Deadly Inherited Metabolic Disorders

Researchers will use two-photon cellular imaging in mouse models of two genetically determined “lysosomal storage” diseases, to determine how the diseases lead to accumulation of unprocessed metabolic products from brain cells, resulting in early childhood death.  Additionally, the researchers will graft into the mouse models embryonic “progenitor” cells, which may evolve into cells that clear away the aberrant metabolic products, and will monitor the effectiveness of this treatment through two-photon imaging that extends over several weeks.

Children with genetically determined lysosomal storage diseases, including Tay-Sach’s and Krebbe’s diseases, lack certain enzymes.  Without these enzymes, the children’s brain cells accumulate unprocessed metabolic products, while failing to produce the intended metabolic products needed.  Ordinarily, metabolic products are cleared away from brain cells by “astrocytes,” but in these children this does not occur.  The investigators hypothesize that the accumulation of the unprocessed metabolic products disrupts communication between astrocytes and between astrocytes and brain cells.  They also hypothesize that, by grafting in embryonic progenitor cells, these cells will evolve into functioning astrocytes, which can deliver the missing enzymes and produce clearance of the aberrant metabolic products.  The researchers will use two-photon imaging to test both hypotheses in mouse models of Tay-Sachs and Krabbe’s diseases.

Significance:  If grafting embryonic cells into mouse models of these two deadly lipid storage diseases reverses cell damage, the animal model research would provide important evidence for possible human studies of this treatment approach.

Abstract

Two-photon Imaging as a Platform for the Real-time Evaluation of Human Glial Progenitor Cell Engraftment in the Lysosomal Storage Disorders

The childhood lysosomal storage disorders comprise a group of disorders in which congenital enzymatic deficiencies lead to the accumulation of unprocessed metabolic substrates, which ultimately cause the widespread death of both neurons and glial cells in the brain. These are overwhelmingly diseases of infants and young children, and most result in the unchecked death of the afflicted children. Over the past few years, we have addressed this issue from the standpoint of establishing a cell therapeutic approach to relieving the central nervous system manifestations of the lysosomal storage disorders and of other associated diseases of the cerebral white matter, the pediatric leukodystrophies. This proposal to the Dana Foundation is intended to capitalize upon recent advances in two-photon imaging technology, to test our hypothesis that the misaccumulation of lysosomal storage products in the lysosomal storage diseases may disrupt inter-glial and glial-neuronal communication, and thereby contribute to the poorly understood functional deficits of these disorders.

Using mouse models of both Sandhoff's/Tay-Sachs and Krabbe's diseases, we shall also test the corollary hypothesis that perinatal engraftment by purified preparations of glial progenitor cells might be sufficient to mitigate lysosomal storage product deposition in diseased host cells. To this end, we shall use 2-photon imaging to follow the treatment-associated clearance of mis-accumulated storage products in live host cortices. Together, these studies promise a wealth of new insight into the pathophysiology of neural dysfunction in the lysosomal storage diseases, to be acquired in the context of a potentially exciting new therapeutic strategy based on perinatal brain engraftment by glial progenitor cells.