Neuronal replacement therapy: previous achievements and challenges ahead

Abstract

Lifelong neurogenesis and incorporation of newborn neurons into mature neuronal circuits operates in specialized niches of the mammalian brain and serves as role model for neuronal replacement strategies. However, to which extent can the remaining brain parenchyma, which never incorporates new neurons during the adulthood, be as plastic and readily accommodate neurons in networks that suffered neuronal loss due to injury or neurological disease? Which microenvironment is permissive for neuronal replacement and synaptic integration and which cells perform best? Can lost function be restored and how adequate is the participation in the pre-existing circuitry? Could aberrant connections cause malfunction especially in networks dominated by excitatory neurons, such as the cerebral cortex? These questions show how important connectivity and circuitry aspects are for regenerative medicine, which is the focus of this review. We will discuss the impressive advances in neuronal replacement strategies and success from exogenous as well as endogenous cell sources. Both have seen key novel technologies, like the groundbreaking discovery of induced pluripotent stem cells and direct neuronal reprogramming, offering alternatives to the transplantation of fetal neurons, and both herald great expectations. For these to become reality, neuronal circuitry analysis is key now. As our understanding of neuronal circuits increases, neuronal replacement therapy should fulfill those prerequisites in network structure and function, in brain-wide input and output. Now is the time to incorporate neural circuitry research into regenerative medicine if we ever want to truly repair brain injury.

In Vitro Targeting and Imaging of Neurogenic Differentiation in Mouse Bone-Marrow Derived Mesenchymal Stem Cells with Superparamagnetic Iron Oxide Nanoparticles

“…Particularly, D1 Mesenchymal stem cells (MSCs) can cause auto-regeneration and differentiation of other mesenchymal systems and are used to restore cartilage in the orthopedic area [7]. Mesenchymal stem cells (MSCs) have recently been evaluated for use in cellular repair after central nervous system injury [8,9]. MSCs are derived from the bone marrow and can self-renew and differentiate into several distinct mesenchymal lineages [10][11][12].…”

Transcription factor programming of human ES cells generates functional neurons expressing both upper and deep layer cortical markers

“…The human cortex is affected by several debilitating acute and chronic neurodegenerative disorders such as stroke, traumatic brain injury, amyotrophic lateral sclerosis and Alzheimer’s disease, which target specific types of cortical neurons. Emerging evidence indicates that stem cells and reprogrammed cells can be used to generate human cortical neurons both for cell replacement by transplantation, and for disease modeling and drug screening [ 1 , 2 ]. Several laboratories have established in vitro protocols for the derivation of excitatory pyramidal neurons, the principal type of neuron in the adult cortex, from human pluripotent stem cells (hPSCs) [ 3 – 5 ].…”

New approaches for brain repair—from rescue to reprogramming

“…Brain repair from endogenous sources has been considered for some time 63 , especially after the (re-) discovery of adult neurogenesis and proof for its existence in the human brain 64,65 , prompting attempts for recruitment of new neurons from endogenous neurogenic niches to achieve repair in the injured brain 66,67 (Figure 3). Simply recruiting new neurons from active neurogenic sites appears intuitively to be the most promising and easiest to achieve.…”