A Spacetime Odyssey of Neural Progenitors to Generate Neuronal Diversity / 神经科学通报·英文版

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.

Transplantation of neural stem cells: cellular & gene therapy for hypoxic-ischemic brain injury

We have tracked the response of host and transplanted neural progenitors or stem cells to hypoxic-ischemic (HI) brain injury, and explored the therapeutic potential of neural stem cells (NSCs) injected into mice brains subjected to focal HI injury. Such cells may integrace appropriately into the degenerating central nervous system (CNS), and showed robust engraftment and foreign gene expression within the region of HI inury. They appeared to have migrated preferentially to the site of ischemia, experienced limited proliferation, and differentiated into neural cells lost to injury, trying to repopulate the damaged brain area. The transplantation of exogenous NSCs may, in fact, augment a natural self-repair process in which the damaged CNS "attempts" to mobilize its own pool of stem cells. Providing additional NSCs and trophic factors may optimize this response. Therefore, NSCs may provide a novel approach to reconstituting brains damaged by HI brain injury. Preliminary data in animal models of stroke lends support to these hypotheses.

THE PROLIFERATION AND DIFFERENTIATION OF NEURAL PROGENITORS IN THE SN OF PARKINSONIAN RATS / 解剖学报

Objective To observe the proliferation and differentiation of the neural progenitors in the midbrain substantia nigra(SN) of adult rat when dopaminergic neurons(DA neurons) were destroyed. Methods The Parkinson disease model(PD model) was induced in adult SD rats by steriotaxic injection of 6-OHDA into the right striatum,and then assessed by behavioral analysis to screen the qualified models.After varied survival period,the brain of model rats were perfused and fixed by 4% paraformaldehyde,moved the segment of SN,embedded with paraffin and coronally sectioned continuously.The microsections were processed by immunohistochemistry labeling separately the neural progenitors with anti-nestin monoclonal antibody,the dividing cells with anti-PCNA(proliferation cell nuclear antigen),the neuronal precursors with anti-Tuj1(?-tubulin isotype Ⅲ),and DA neurons with anti-TH(tyrosine hydroxylase).The labeled cells were counted under microscope and analyzed statistically.(Results It) was found in the right SN of PD model rats that: 1.Nestin positive(Nestin~+) cells appeared 10d after 6-OHDA injection,became abundant on 14d,declined in number on 17d,and disappeared on 21d.2.Weakly positive PCNA(PCNA~+) cells appeared on 7d.PCNA~+ cells were abundant on 14d,decreased in number from 21d,with only a few positive cells noticed on 28d.3.Tuj1 positive cells appeared in small number on 10d,became abundant on 14d,decreased in number from 17d and dropped nearly to zero on 21d.4.The number of TH positive neurons was significantly less than the normal control(by 24%) on 7d,and became even less as time elapsed.Conclusion When 6-OHDA is injected into the striatum of adult rats to cause degeneration and death of the DA neurons there,there would be a certain period of time in which a number of neural progenitors will be induced to proliferate actively and differentiate toward neuronal cells(except DA neurons).