A conversation with Dr. Zaal Kokaia, PhD, Professor of Experimental Medical Research and the Head of the Laboratory of Stem Cells & Restorative Neurology at the Lund University Stem Cell Center in Sweden.
Interviewed by Gurmeen Kaur, MBBS, Vascular Neurology Fellow, Icahn School of Medicine at Mount Sinai.
They will be discussing the paper “Customized Brain Cells for Stroke Patients Using Pluripotent Stem Cells,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.
Dr. Kaur: Thank you for this excellent review on evolving approaches in stroke regenerative medicine. Could you please summarize the review for a layperson?
Dr. Kokaia: Currently, stem cells are considered a promising source for development of new therapies for stroke patients. In experiments with transplantation of stem/progenitor cells in stroke, tissue repair and promotion of post-stroke functional recovery can occur through replacement of dead or damaged neurons and glia, production of growth factors and cytokines, and stimulation of the intrinsic progenitors. Embryonic stem cells or skin-derived pluripotent cells can be transformed into early neural precursors with relatively simple methods. However, recently it became possible to take these pluripotent stem cells and differentiate them into more specific types of neurons and glia. In our paper, we discuss how to use this approach for post-stroke regeneration — how to make and replace specific neurons and glia cells in a stoke-damaged brain through transplantation and restore brain function.
Dr. Kaur: In the paper, you mentioned that stem cell-based therapy will most likely be needed particularly for patients with cortical or combined cortico-subcortical lesions. What is the rationale behind excluding striatal or exclusively subcortical infarcts?
Dr. Kokaia: We have previously carried out clinical study that illustrated that stroke patients with only striatal lesion are relatively rare. Normally, their functional impairments are mild with very good spontaneous recovery. Therefore, we believe that stem therapy-based approaches aiming for reconstruction of lesioned neuronal network might be more appropriate for those patients who have cortical or combined cortico-subcortical lesions.
Dr. Kaur: Based on the review, it seems that the timing of transplantation of the human induced pluripotent stem cells (iPSCs) is critical to their integration into the brain. Could you tell us a little more about that?
Dr. Kokaia: You are right, timing seems to be important. During the first days after stroke, there is very strong pro-inflammatory response in the brain, and this time window might not be optimal for the transplantation, survival and integration of neuronal progenitors. We believe that sub-acute or early chronic phase of stroke might be more suitable for such treatment considering that regenerative processes are still ongoing and brains undergo plastic re-arrangements to cope with stroke-induced lesion.
Dr. Kaur: What are the challenges faced by basic scientists when trying to develop customized pluripotent stem cells for stroke recovery?
Dr. Kokaia: The major challenge for us is to develop the cells with very specific features. If you want to reconstruct brain network involving cortex, there are so many different types of cortical neurons that it is difficult to know which type needs to be provided to the brain in order to achieve optimal reconstruction. At the same time, it is very difficult to produce human cortical neuron with very defined structural and functional properties.
Dr. Kaur: Have any ethical concerns been brought up during the development of the field of regenerative medicine, and, if so, how have they been addressed?
Dr. Kokaia: When using pluripotent stem cells for intracerebral transplantation, the risk of tumorigenicity remains a major ethical concern. However, generation of specific types of neurons and glial cells or pre-differentiation of pluripotent cells before delivering to the brain substantially decreases, if not fully abolishes, the risk of tumor formation. In addition, sorting of pre-differentiated cells with no proliferative or tumorigenic properties, as well as testing of these cells in tumor formation and toxicity assays, provides additional security. Expression of potential tumorigenic genes and checking the karyotype of pluripotent stem cell-derived neural cells are also commonly used measures to avoid any risks of tumor formation.
Dr. Kaur: Given that human iPSCs can differentiate into astrocytes and oligodendrocyte precursor cells, what neurological conditions, other than stroke, may potentially benefit from this in the future?
Dr. Kokaia: In theory, virtually, any acute or chronic neurological diseases associated with neuronal loss or glia cell pathology can benefit from the possibility to generate specific type of neurons or glial cells. However, very vigorous and comprehensive basic and clinical studies will be required to come up with viable and efficient, but at the same time safe, therapeutic strategy for each disease. Moreover, most likely not all the patients with a given disease might be suitable for cell therapy, and identification of relevant cohort of patients who can benefit from given treatment is also a very important task.
A particular challenge for a glial replacement therapy is the disease target. The most devastating stroke condition to affect glial cells is white matter stroke or vascular dementia. This is a challenging condition to treat with a stem cell therapy, as the stem cell must differentiate into a glial cell and also migrate substantially in the brain, because the disease is quite diffuse. Unlike large artery stroke, white matter stroke is distributed throughout the cerebral white matter.
Dr. Kaur: How far are we from customized stroke stem cell therapy being mainstream and available for translational research?
Dr. Kokaia: It will take some time for customized stroke stem cell therapy to become available for clinical application. There are still a lot of questions that need to be addressed. However, things are moving forward, and we sincerely hope that this approach sooner or later will find its way to the clinic. The upcoming clinical trials with pluripotent stem cell-derived dopaminergic cells for Parkinson’s disease will certainly help us to navigate through complex translational pathways to benefit stroke patients with new stem cell-based therapies.
Dr. Kaur: Thank you very much for participating in the Blogging Stroke interview.