Nanomatrix helps neural stem cells self-organize into functional structures affected in PD
Researchers from the Hong Kong Baptist University (HKBU) have developed an extracellular inorganic nanomatrix that induces rapid and specific differentiation of neural stem cells (NSCs) into miniature substantia nigra-like structures (mini-SMLSs) without the use of growth factors (GFs). Transplantation of differentiated neurons from these mini‐SNLSs has shown an early and progressive amelioration of Parkinson’s desease (PD) in rats.
“Substantia nigra is a complex and critical region of the brain where PD arises from the degeneration of dopaminergic neurons,” wrote the researchers. “The construction of mini‐SNLSs, which comprise mainly dopaminergic and GABAergic neurons and a small population of glutamatergic neurons, is highly significant, given the potential uses in the screening of neurological drugs and development of curative stem-cell therapies for PD.” [Adv Sci (Weinh), doi: https://doi.org/10.1002/advs.201901822]
Inorganic sculptured extracellular nanomatrices (iSECnMs) were constructed from silica by glancing angle deposition and sculptured into nanozigzags (NZs). [Nanoscale 2014;6:9401] “Silica is a biocompatible, naturally abundant, and inexpensive substance. The associated protocol is effective, rapid, specifically controllable, and reproducible,” noted the researchers. [Nanoscale 2012;4:486]
Isolated NSCs were mediated in vitro on silica inorganic sculptured extracellular nanomatrices (iSECnMs) in commercial neurobasal medium; no additional GFs were added. In the absence of chemical manipulation, NSC differentiation was induced by physical stimulation via extracellular matrix topography and subsequent activation of multiple signalling pathways. Scanning electron microscopy revealed that the differentiated neuronal cells appeared to spread over and strongly adhere to the sculptured nanostructures. “The NZ‐promoted self‐organization of the mini‐SNLS can be attributed to topographic cues,” wrote the researchers.
In a 2-week culture, NZs induced the differentiation and maturation of NSCs into mini‐SNLSs, which exhibited good survival and phenotypic stability after transplantation into adult rat brains, enabling a study of their therapeutic effects in rat models of PD.
Before transplantation of mini‐SNLSs, 6‐hydroxydopamine (6‐OHDA)-treated rats with a unilateral lesion on the left side of the medial forebrain exhibited severe apomorphine‐induced motor asymmetry. After transplantation of mini‐SNLSs, the rats exhibited a progressive reduction in apomorphine‐induced rotations over the 18-week study period. No tumour‐like and tumorigenic characteristics were detected. “These results illustrate that the silica NZ‐mediated, self‐organized mini‐SNLSs induced early and positive therapeutic effects in 6‐OHDA lesion‐induced PD rats,” stated the researchers.
Compared with previous studies of the transplantation of chemically or genetically manipulated induced pluripotent stem cells (iPSCs)‐derived progenitors or homogeneous iPSC‐derived dopaminergic neurons, the motor symptom amelioration achieved by transplanting neurons from the mini‐SNLSs was initiated at a much earlier time point: 8 weeks vs ≥16 weeks post‐transplantation. [Nat Commun 2016;7:13097] “The results of recent studies indicate that transplants of brain or other organ‐like structures are much more biofunctional than homogeneous populations of neurons or cells,” commented the researchers. [N Engl J Med 2019:380;569]
According to the researchers, the mini‐SNLSs appear to be very safe for potential clinical applications, given the following aspects: 1) the mini‐SNLSs self‐organize on iSECnMs comprising biocompatible silica nanostructures; 2) the lack of traditional GFs minimizes undesirable effects in clinical applications; 3) mini‐SNLSs are derived from nongenetically manipulated NSCs and therefore confer a lower risk of tumorigenicity than iPSCs; and 4) the transplantation of mini‐SNLSs composed of mature and differentiated neurons allays the risks of carcinogenicity and unwanted differentiation in vivo.