Correcting Lipoprotein Lipase Deficiency with Allogeneic Bone Marrow Stromal Cells
P.R. Vulliet1,3; S.M. Halloran1; K.M. Tallon1; D.L. Bee1; L.A. Lyons2; A.J. Fascetti1; P.S. Rosman3
To determine if injection of allogeneic lipoprotein lipase (LPL) expressing bone marrow stromal cells (MSCs) will correct metabolic deficiencies in LPL-/- cats.
Bone marrow was harvested from LPL+/+ cats, amplified in culture and fifty million MSCs injected into LPL-/- cats. Two weeks later, an identical injection was repeated from the same preparation of MSCs. Plasma turbidity, triglycerides, cholesterol and lipase activity was monitored at various times prior to and following the injection of the MSCs.
Injection of MSCs resulted in a decrease in the plasma lipid profile three to five days following administration. Following the first injection, there was a modest decrease in plasma turbidity. The second injection resulted in a much greater decrease in plasma turbidity and lipids. This enhanced response following the second injection suggests that there might be an accumulation of LPL+/+ cells somewhere in the cat, most likely in the bone marrow. To confirm that the observed decrease in plasma lipids resulted from circulating lipoprotein lipase activity from the injected MSC's, plasma samples were collected and LPL activity measured. Following the first administration of MSCs, a slight increase in LPL was observed and following the second a larger increase in LPL activity was noted. Both of these values correlated with the clearing of plasma turbidity. Further monitoring of this cat for six months revealed that the effect on plasma lipids lasted approximately three months.
Injection of allogeneic MSCs corrects the LPL-/- genetic defect and transiently returns the plasma lipid profile to near normal in a dose dependent manner. Multiple injections of allogeneic MSCs demonstrate additively and increased duration of effect. Behavioral modifications and additional benefits were also observed. Using this dose and injection protocol, the bi- or tri-phasic duration of therapeutic action appears to last approximately three months. This is a very powerful and robust animal model for studying cytokinetics and cytotherapeutics as well as transiently correcting genetic deficits.
This research was support by the Center for Companion Animal Research at U C Davis and the Winn Feline Research Foundation.