Functional reconstruction of the impaired cortex and motor function by hMGEOs transplantation in stroke.

Stroke is the leading cause of death and long-term disability worldwide. But treatments are not available to promote functional recovery, and efficient therapies need to be investigated. Stem cell-based therapies hold great promise as potential technologies to restore function in brain disorders. Loss of GABAergic interneurons after stroke may result in sensorimotor defects. Here, by transplanting human brain organoids resembling the MGE domain (human MGE organoids, hMGEOs) derived from human induced pluripotent stem cells (hiPSCs) into the infarcted cortex of stroke mice, we found that grafted hMGEOs survived well and primarily differentiated into GABAergic interneurons and significantly restored the sensorimotor deficits of stroke mice for a long time. Our study offers the feasibility of stem cell replacement therapeutics strategy for stroke.

The telomerase inhibitor AZT enhances differentiation and prevents overgrowth of human pluripotent stem cell-derived neural progenitors.

Human pluripotent stem cell (hPSC)-based cell-replacement therapy has emerged as a promising approach for addressing numerous neurological diseases. However, hPSC transplantation has the potential to cause human cell overgrowth and cancer, which represents a major obstacle to implementing hPSC-based therapies. Inhibition of the overgrowth of transplanted cells could help reduce the risk for hPSC transplantation-induced tumorigenesis. In this study, we report that the telomerase inhibitor azidothymidine (3'-azido-3'-deoxythymidine; AZT) enhances the differentiation of cortical neurons and significantly suppresses the proliferation of hPSC-derived cortical progenitors. Using human embryonic stem cells and induced pluripotent stem cells in culture, we found that AZT effectively reduces the number of dividing progenitors without inducing cell death. Furthermore, AZT promoted differentiation of cortical progenitors and maturation of cortical neurons. Of note, AZT-pretreated, hPSC-derived neural progenitors exhibited decreased proliferation and increased differentiation into cortical neurons when transplanted into the mouse brain. In summary, our findings indicate that AZT prevents the overgrowth of hPSC-derived neural precursors and enhances the differentiation of cortical neurons in both cell cultures and hPSC-transplanted mouse brain. We propose that our work could inform clinical applications of hPSC-based cell therapy.

Saturable absorber based on a single mode fiber - graded index fiber - single mode fiber structure with inner micro-cavity.

An Er-doped mode-locked fiber laser with a saturable absorber based on single mode - graded index multimode - single mode fiber (SMF-GIMF-SMF) with inner micro-cavity is demonstrated. The modulation depth of the saturable absorber was measured to be 1.9% when the SMF-GIMF-SMF structure is bent to a certain state. Such a simple saturable absorber enables the mode-locking operation in a ring Er-doped fiber laser and ultrafast pulses with pulse energy of 0.026 nJ and pulse width of 528 fs at the fundamental repetition rate of 14.34 MHz can be generated. In addition, the harmonic mode-locking operation can also be achieved.

Stretched graded-index multimode optical fiber as a saturable absorber for erbium-doped fiber laser mode locking.

A novel mode-locking method based on the nonlinear multimode interference in the stretched graded-index multimode optical fiber (GIMF) is proposed in this Letter. The simple device geometry, where the light is coupled in and out of the stretched GIMF via single-mode fibers, is demonstrated to exhibit the temporal intensity discrimination required for mode locking. The nonlinear saturable absorber (SA) characteristics of the device are controllable by simply adjusting the strength of the stretching applied. The modulation depth of the device, which consists of ∼23.5 cm GIMF, is tuned from 10.37% to 22.27%. Such a simple SA enables the wavelength-switchable mode-locking operation in a ring Er-doped fiber laser, and ultrafast pulses with a pulse width of 506 fs at 1572.5 nm and 416 fs at 1591.4 nm were generated. The versatility and simplicity of the SA device, together with the possibility of scaling the pulse energy, make it highly attractive in ultrafast photonics.

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.

Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

[Joint time-frequency analysis for removing the spectral interference of terahertz].

Conventional Fourier-transform mixes the frequency components of the entire temporal terahertz waveform in one frequency domain; therefore, it cannot distinguish the terahertz frequency in the main pulse from the noise frequency in the pulse tail. Thus traditional Fourier-transform produces inconsistent spectra from different scanning lengths of terahertz pulse. And the interference spectrum appears when the THz echo pulse is recorded. The authors applied wavelet-transform and removed the inconsistent spectra and the interference spectra. Wavelet-transform technique exhibited the local frequency of THz in different time locations. This technique would find applications in THz time-resolved spectroscopy.

Enhanced derivation of human pluripotent stem cell-derived cortical glutamatergic neurons by a small molecule.

Human pluripotent stem cells (hPSCs) play important role in studying the function of human glutamatergic neurons and related disease pathogenesis. However, the current hPSC-derived cortical system produced a significant number of inhibitory GABAergic neurons that reduced the purity of excitatory neurons. In this study, we established a robust hPSC-derived cortical neurogenesis system by applying the SHH inhibitor cyclopamine. Cyclopamine specified the dorsal cortical fate in a dose-dependent manner and enhanced the generation of cortical glutamatergic neurons, expressing PAX6, TBR1, TBR2, CTIP2, SATB2, and vesicular glutamate transporters (vGLUT). In contrast, the ventral patterning was inhibited and the GABAergic neurons were significantly reduced to 12% with the treatment of cyclopamine. In addition, we applied our current method to generate trisomy 21 iPSC-derived glutamatergic neurons that showed a robust reduction of vesicular glutamate transporters in the glutamatergic neurons with trisomy 21, revealing the developmental deficits in cortical glutamatergic neurons. Our method enriched the generation of cortical glutamatergic neurons which may facilitate the study of human neurological diseases and cell therapy.

Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells.

BACKGROUND: Basal forebrain cholinergic neurons (BFCNs) play critical roles in learning, memory and cognition. Dysfunction or degeneration of BFCNs may connect to neuropathology, such as Alzheimer's disease, Down's syndrome and dementia. Generation of functional BFCNs may contribute to the studies of cell-based therapy and pathogenesis that is related to learning and memory deficits. NEW METHOD: Here we describe a detail method for robust generation of BFCNs from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). In this method, BFCN progenitors are patterned from hESC or hiPSC-derived primitive neuroepithelial cells, with the treatment of sonic hedgehog (SHH) or combination with its agonist Purmorphamine, and by co-culturing with human astrocytes. RESULTS: At day 20, ∼90% hPSC-derived progenitors expressed NKX2.1, which is a transcriptional marker for MGE. Moreover, around 40% of NKX2.1+ cells co-expressed OLIG2 and ∼15% of NKX2.1+ cells co-expressed ISLET1, which are ventral markers. At day 35, ∼40% neurons robustly express ChAT, most of which are co-labeled with NKX2.1, ISLET1 and FOXG1, indicating the basal forebrain-like identity. At day 45, these neurons express mature neuronal markers MAP2, Synapsin, and VAChT. COMPARISON WITH EXISTING METHOD(S): In this method, undefined conditions including genetic modification or cell-sorting are avoided. As a choice, feeder free conditions are used to avoid ingredients of animal origin. Moreover, Purmorphamine can be substituted for SHH to induce ventral progenitors effectively and economically. CONCLUSION: We provide an efficient method to generate BFCNs from multiple hPSC lines, which offers the potential application for disease modeling and pharmacological studies.

Efficient generation of region-specific forebrain neurons from human pluripotent stem cells under highly defined condition.

Human pluripotent stem cells (hPSCs) have potential to differentiate to unlimited number of neural cells, which provide powerful tools for neural regeneration. To date, most reported protocols were established with an animal feeder system. However, cells derived on this system are inappropriate for the translation to clinical applications because of the introduction of xenogenetic factors. In this study, we provided an optimized paradigm to generate region-specific forebrain neurons from hPSCs under a defined system. We assessed five conditions and found that a vitronectin-coated substrate was the most efficient method to differentiate hPSCs to neurons and astrocytes. More importantly, by applying different doses of purmorphamine, a small-molecule agonist of sonic hedgehog signaling, hPSCs were differentiated to different region-specific forebrain neuron subtypes, including glutamatergic neurons, striatal medium spiny neurons, and GABA interneurons. Our study offers a highly defined system without exogenetic factors to produce human neurons and astrocytes for translational medical studies, including cell therapy and stem cell-based drug discovery.