Iacovitti Research

Our lab focus is in the fields of stem cell biology and neuroprotection with an emphasis on Parkinson’s disease (PD) and stroke models. Human induced pluripotent stem cells (iPSCs, left), with their potential to generate autologous patient-derived cells (such as, dopamine neurons in green, right) hold great promise for the study and treatment of a host of devastating diseases, including PD. Endogenous stem cells present in the adult brain are likewise important in repair particularly after acute injury like stroke. Our lab has concentrated on the molecular and cellular changes in the blood-brain-barrier that ultimately lead to regulation of stem cell proliferation and neuronal differentiation after stroke. We also have focused our studies on the discovery of novel factors capable of protecting neurons at risk for dying during progressive disease (PD) or after injury (stroke).

Our lab studies focus on the differentiation of CNS neurons from stem cells, in particular, the dopamine neuron. These studies include epigenetic and environmental regulation of cell phenotype. Our goals are 1) defining the underlying principles governing the differentiation of the midbrain dopamine neuron, the cell lost in Parkinson’s disease (PD); 2) using differentiated patient- specific iPS cells for PD modeling and drug discovery in culture; and 3) translating these discoveries into therapies to treat PD in patients.

PD is a well-studied neurodegenerative disease which is characterized by the selective degeneration of dopamine neurons of the substantia nigra pars compacta (SN), while the DA neurons of the neighboring ventral tegmental area (VTA) are relatively spared. In addition to studying intrinsic differences between SN and VTA neurons, our lab also examines neighboring astrocytes, which are known to release a variety of neurotrophic factors. We recently showed that the astrocytes from these two regions are regionally specified, with VTA astrocytes uniquely producing the growth factor GDF-15 which can rescue both SN and VTA DA neurons from PD challenge. These findings raise the intriguing possibility that the vulnerability of specific populations of neurons to disease risk factors may not stem entirely from neuron-intrinsic susceptibilities but also from differences in support from their local astrocytic microenvironments.

In addition to midbrain neurons and astrocytes, microglia (MG), the resident immune cells of the brain, likely play a key role in the degeneration of SN neurons in PD. Intriguingly, SN houses greater numbers of MG and fewer astrocytes while the neighboring VTA is characterized by low numbers of MG and a high number of astrocytes. Is life or death then a balancing act between damaging MG and protective astrocytes? Using PD iPSC models and the hTH-GFP reporter rat we would like to answer: 1) Are MG regionally distinct like midbrain astrocytes and neurons, expressing specific cell surface markers, transcription factors, cytokines, etc.? 2) Can we adapt what we learn from the rat model to a human iPSCs system? 3) Can we examine the roles of neurons, astrocytes, MGs in PD susceptibility using PD patient-specific iPS cells?