Stroke alters behavior of human skin-derived neural progenitors after transplantation adjacent to neurogenic area in rat brain

This requires an update to our stroke strategy on stem cells. Ask your stroke leader when that strategy will be updated. But is this useful for stroke recovery? Inquiring minds want to know.
https://stemcellres.biomedcentral.com/articles/10.1186/s13287-017-0513-6

• Carlos de la Rosa-Prieto,
• Cecilia Laterza,
• Ana Gonzalez-Ramos,
• Somsak Wattananit,
• Ruimin Ge,
• Olle Lindvall,
• Daniel Tornero†Email authorView ORCID ID profile and
• Zaal Kokaia†

†Contributed equally

Stem Cell Research & Therapy20178:59

DOI: 10.1186/s13287-017-0513-6

©  The Author(s). 2017

Received: 10 December 2016

Accepted: 17 February 2017

Published: 9 March 2017

Abstract

Background

Intracerebral transplantation of human induced pluripotent stem cells (iPSCs) can ameliorate behavioral deficits in animal models of stroke. How the ischemic lesion affects the survival of the transplanted cells, their proliferation, migration, differentiation, and function is only partly understood.

Methods

Here we have assessed the influence of the stroke-induced injury on grafts of human skin iPSCs-derived long-term neuroepithelial-like stem cells using transplantation into the rostral migratory stream (RMS), adjacent to the neurogenic subventricular zone, in adult rats as a model system.

Results

We show that the occurrence of an ischemic lesion, induced by middle cerebral artery occlusion, in the striatum close to the transplant does not alter the survival, proliferation, or generation of neuroblasts or mature neurons or astrocytes from the grafted progenitors. In contrast, the migration and axonal projection patterns of the transplanted cells are markedly influenced. In the intact brain, the grafted cells send many fibers to the main olfactory bulb through the RMS and a few of them migrate in the same direction, reaching the first one third of this pathway. In the stroke-injured brain, on the other hand, the grafted cells only migrate toward the ischemic lesion and virtually no axonal outgrowth is observed in the RMS.

Conclusions

Our findings indicate that signals released from the stroke-injured area regulate the migration of and fiber outgrowth from grafted human skin-derived neural progenitors and overcome the influence on these cellular properties exerted by the neurogenic area/RMS in the intact brain.

Keywords

Adult neurogenesis Human skin-derived cells Pluripotent Rostral migratory stream Stroke Subventricular zone Transplantation

Background

Intracerebral transplantation of induced pluripotent stem cells (iPSCs) or their derivatives, generated by reprogramming human somatic cells, can reverse behavioral deficits in experimental stroke models (for references, see [1]). Improvements were detected early after transplantation, indicating that they were not due to neuronal replacement but to other mechanisms such as modulation of inflammation, and promotion of plastic responses and neovascularization. However, we recently showed that human iPSC-derived long-term neuroepithelial-like stem cells (lt-NESCs) transplanted into stroke-injured cortex can differentiate to form functional cortical neurons, which receive afferent inputs from appropriate brain areas and respond to mechanical stimulation of nose and paw [2]. It remains to be demonstrated, though, that this incorporation into host neural circuitry contributes to the long-term functional recovery after stroke.

A fundamental question, also in a clinical-therapeutical perspective, is how the stroke-induced injury affects the survival, proliferation, migration, neuronal differentiation, integration and function of the grafted human iPSC-derived cells. Implantation of the cells in the rostral migratory stream (RMS), close to one of the main neurogenic areas in the brain, the subventricular zone (SVZ), seems to be a useful model system to address these issues. In the SVZ, neural stem/progenitor cells form new neurons that travel, via the RMS, toward the main olfactory bulb (MOB) [3], where they integrate as interneurons in the granule and periglomerular cell layers. Several cues have been identified which take part in this process [4, 5, 6] and may regulate the behavior also of cells transplanted close to the SVZ into the adult rodent brain. For example, differentiated neurons from a human teratocarcinoma send their axons through the RMS and in association with ipsilateral and contralateral white matter pathways [7]. When implanting human skin-derived iPSCs close to the SVZ in adult intact brains, most of the grafted cells migrate via the RMS. In contrast, oligodendrocytes implanted do not migrate along the RMS but follow the white matter pathways along the corpus callosum and internal capsule [8]. Whether the occurrence of an ischemic lesion affects the migration, axonal outgrowth or other properties of human iPSCs implanted close to the SVZ is unknown.

Here we have explored the role of the ischemic injury for the behavior of human iPSC-derived lt-NESCs after transplantation into the RMS, adjacent to the neurogenic SVZ, in intact and stroke-damaged rats. We demonstrate that the stroke-induced lesion markedly alters the patterns of axonal outgrowth and migration of the grafted cells, whereas survival, proliferation, and generation of neuroblasts, mature neurons or astrocytes are unaffected.

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