Primary familial brain calcification (PFBC) is a rare, progressive central nervous system (CNS) disorder without a cure, and the current treatment methodologies primarily aim to relieve neurological and psychiatric symptoms of the patients. The disease is characterized by abnormal bilateral calcifications in the brain, however, our mechanistic understanding of the biology of the disease is still limited. Determining the roles of the specific cell types and molecular mechanisms involved in the pathophysiological processes of the disease is of great importance for the development of novel and effective treatment methodologies. There is a growing interest in the involvement of astrocytes in PFBC, as recent studies have suggested that astrocytes play a central role in the disease and that functional defects in these cells are critical for the development and progression of the disease. This review aims to discuss recent findings on the roles of astrocytes in PFBC pathophysiology, with a focus on known expression and roles of PFBC genes in astrocytes. Additionally, we discuss the importance of human astrocytes for PFBC disease modeling, and astrocytes as a potential therapeutic target in PFBC. Utilization of species-specific and physiologically relevant PFBC model systems can open new avenues for basic research, drug development, and regenerative medicine.

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovascular diseases, and traumatic brain injuries, are among the major disorders influencing human health, currently with no effective therapy. Due to the low regeneration capacity of neurons, insufficient secretion of neurotrophic factors, and the aggravation of ischemia and hypoxia after nerve injury, irreversible loss of functional neurons and nerve tissue damage occurs. This damage is difficult to repair and regenerate the central nervous system after injury. Neural stem cells (NSCs) are pluripotent stem cells that only exist in the central nervous system. They have good self-renewal potential and ability to differentiate into neurons, astrocytes, and oligodendrocytes and improve the cellular microenvironment. NSC transplantation approaches have been made for various neurodegenerative disorders based on their regenerative potential. This review summarizes and discusses the characteristics of NSCs, and the advantages and effects of NSCs in the treatment of brain diseases and limitations of NSC transplantation that need to be addressed for the treatment of brain diseases in the future.

Lysosomal storage disorders (LSDs) are rare inborn errors of metabolism caused by defects in lysosomal function. These diseases are characterized by accumulation of completely or partially degraded substrates in the lysosomes leading to cellular dysfunction of the affected cells. Currently, enzyme replacement therapies (ERTs), treatments directed at substrate reduction (SRT), and hematopoietic stem cell (HSC) transplantation are the only treatment options for LSDs, and the effects of these treatments depend strongly on the type of LSD and the time of initiation of treatment. However, some of the LSDs still lack a durable and curative treatment. Therefore, a variety of novel treatments for LSD patients has been developed in the past few years. However, despite significant progress, the efficacy of some of these treatments remains limited because these therapies are often initiated after irreversible organ damage has occurred.Here, we provide an overview of the known effects of LSDs on stem cell function, as well as a synopsis of available stem cell-based cell and gene therapies that have been/are being developed for the treatment of LSDs. We discuss the advantages and disadvantages of use of hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and induced pluripotent stem cell (iPSC)-related (gene) therapies. An overview of current research data indicates that when stem cell and/or gene therapy applications are used in combination with existing therapies such as ERT, SRT, and chaperone therapies, promising results can be achieved, showing that these treatments may result in alleviation of existing symptoms and/or prevention of progression of the disease. All together, these studies offer some insight in LSD stem cell biology and provide a hopeful perspective for the use of stem cells. Further development and improvement of these stem cell (gene) combination therapies may greatly improve the current treatment options and outcomes of patients with a LSD.

A stable, rapid and effective neural differentiation method is essential for the clinical applications of human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in treating neurological disorders and diseases. Herein, we established a novel and robust monolayer differentiation method to produce functional neural progenitor cells (NPCs) from human ESC/iPSCs on Type I Collagen. The derived cells not only displayed the requisite markers, but also behaved similarly to classic NPCs both in vitro and in vivo. Upon transplantation into traumatic brain injury model, the derived NPCs facilitated recovery from injury. We also found that SMAD signaling stayed down throughout the differentiation process on Type I Collagen, and the pluripotent signals were rapidly downregulated along with raising up of neural early markers on the third day. Meanwhile, ATAC-seq data showed the related mediation of distinct transcriptome and global chromatin dynamics during NPC induction. Totally, our results thus provide a convenient way to generate NPCs from human ESC/iPSCs for neural diseases' treatment.

Alternative cell models of human neural stem cells (hNSCs) have been developed and used for investigations ranging from in vitro experiments to in vivo clinical studies. However, a cell model capable of mimicking the 'normal' state of hNSCs is mandatory in order to extrapolate the results of these studies to humans. In the present study, to select a more suitable hNSC model for developing human‑based experimental platforms, two representative hNSC types were compared, namely human embryonic stem cell (hESC)‑derived hNSCs and ReNcell CX cells, which are well‑characterized immortalized hNSC lines. The hNSCs, differentiated from hESCs via human neuroectodermal sphere (hNES) formation, recapitulated the molecular and cellular phenotypes of hNSCs, including NSC marker expression and terminal neuronal differentiation potential. Comparative analyses of the transcriptome profiles of the hESC‑derived hNESs and ReNcell CX hNSCs showed that the differentiated hNESs were analogous to the ReNcell CX cells, as demonstrated by principal component analysis and hierarchical sample clustering. The hNSC‑specific transcriptome was presented, comprising commonly expressed transcripts between hNESs derived from hESCs and ReNcell CX cells. To elucidate the molecular mechanisms associated with the hNSC identity, the hNSC‑specific transcriptome was analyzed using pathway and functional annotation clustering analyses. The results suggested that hESC‑derived hNESs, an expandable and accessible cell source, may be used as a relevant hNSC model in a wide range of neurological investigations.

Neurological diseases with genetic etiologies result in the loss or dysfunction of neural cells throughout the CNS. At present, few treatment options exist for the majority of neurogenetic diseases. Stem cell transplantation (SCT) into the CNS has the potential to be an effective treatment modality because progenitor cells may replace lost cells in the diseased brain, provide multiple trophic factors, or deliver missing proteins. This review focuses on the use of SCT in lysosomal storage diseases (LSDs), a large group of monogenic disorders with prominent CNS disease. In most patients the CNS disease results in intellectual disability that is refractory to current standard-of-care treatment. A large amount of preclinical work on brain-directed SCT has been performed in rodent LSD models. Cell types that have been used for direct delivery into the CNS include neural stem cells, embryonic and induced pluripotent stem cells, and mesenchymal stem cells. Hematopoietic stem cells have been an effective therapy for the CNS in a few LSDs and may be augmented by overexpression of the missing gene. Current barriers and potential strategies to improve SCT for translation into effective patient therapies are discussed.