Hang Yao, Ph.D.

Dr. Yao’s major interests are understanding the cellular and molecular mechanisms underlying fetal brain development following prenatal opioid exposure and brain functional alterations under low oxygen/ischemia. He has used human brain organoids (Figs1&2) to model maternal opioid exposure in a petri dish and discovered the suppressive effect of methadone on neural network activities (Fig.3). He has also established an in vivo/vitro stroke model to investigate the mechanisms of cell death in the rescuable tissues adjacent to ischemic infarct following stroke (Fig.4).

Figure 1. Cerebral organoids generated from human iPSCs. Left: Human cortical organoids with multiple ventricular-like zones stained with DAPI (blue) and Tuj1 (red). Right: Human astrocyte spheres stained with DAPI (blue), SB100B (red) and GFAP (green).

Figure 2. Generation and characterization of human cortical organoids (hCOs). A, Schematic of cortical organoid generation. Scale bar, 500 μm. B, Representative images of immunostaining on cryosections showing differentiation profile of hCOs over time. Scale bar, 50 μm. C, Representative immunostainings showing a majority of cells in the cortical organoid (10 week of age) are stained with neuronal markers, MAP II (green) and Tuj1 (red). Scale bar, 500 μm. D, Representative immunostainings showing a majority of cells in the cortical organoids were stained with MAP II (green) and VGLUT1 (red). Scale bar, 50 μm. E, Immunostainings showing a GAD67 (green) positive neuron surrounded with many VGLUT1 (red) stained cells. Scale bar, 10 μm. F, Representative images of double immunofluorescence of PSD-95 (red) and synapsin-1 (green), from 12 week old cortical organoid. Merged images show the apposition of the pre-synaptic (green) and post-synaptic (red) boutons. Scale bar, 5 μm.

Figure 3. Methadone suppresses firing of spontaneous action potentials in hCOs. A, An image showing a hCO growing on the microelectrodes on the bottom surface of a multi-electrode array (MEA) plate. B, Representative activity map of MEA recordings showing the alteration of the number of active electrodes under the treatment of a series of methadone dosages. C, Raster plot of a 5 mins-spontaneous activity derived from recordings of hCOs treated with or without methadone with different dosages. Numbers (1, 2, … 64) to the left of representative plots from untreated hCOs denote the channels in the well of a MEA plate.

Figure 4. Stroke models for studying cellular and molecular mechanisms underlying penumbra cell. Left: middle cerebral artery occlusion model showing control mouse brain (left) and the brain with middle cerebral artery occluded (white colored tissues indicates the infarct resulted from the ischemic injury in the mouse brain). Right: mouse hippocampal slice model simulating the ischemic penumbral cell death following the treatment of ischemic solution that mimics the micro-environment of in-vivo penumbra area following ischemic stroke. Pseudocolor (red) showing the propidium iodide stained dead cells.


  1. Negraes PD, Trujillo CA, Yu NK, Wu W, Yao H, Liang N, Lautz J, Kwok E, McClatchy D, Diedrich J, Bartolome S, Herai R, Smith S, Haddad GG, Yates J and Muotri AR. Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy. Mol Psychiatry. 2021 Apr 22. 
  2. Wu W, Yao H, Dwivedi I, Negraes PD, Zhao HW, Wang J, Trujillo CA, Muotri AR and Haddad GG. Methadone Suppresses Neuronal Function and Maturation in Human Cortical Organoids. Front Neurosci. 2020; 14:593248.  
  3. Yao H, Wu W, Cerf I, Zhao HW, Wang J, Negraes PD, Muotri AR and Haddad GG.  Methadone interrupts neural growth and function in human cortical organoids. Stem Cell Res. 2020 12; 49:10206 
  4. Wu W, Yao H, Zhao HW, Wang J and Haddad GG. Down-regulated Inwardly Rectifying K+ Currents in Astrocytes Derived from Patients with Monge's Disease. Neurosci. 2018; 374, 70–79.                                                                                                                
  5. Yao H, Zhao HW, Wang J and Haddad GG. Intracellular pH regulation in iPSCs-derived astrocytes from subjects with Monge's disease. Neurosci. 2018; 375:25-33.
  6. Zhao HW, Perkins G, Yao H, Callacondo D, Appenzeller O, Ellisman M, La Spada A and Haddad GG. Mitochondrial dysfunction in ipsc-derived neurons of subjects with chronic mountain sickness. J Appl Physiol. Dec 21, 2017.
  7. Yao H, Azad P, Zhao HW, Wang J, Poulsen O, Freitas BC, Muotri AR and Haddad GG. The Na+/HCO3- co-transporter is involved in ischemic astrocyte death. Submitted to:  Neurosci. 2016; 339:329-337.
  8. Scortegagna M, Kim H, Li J-L, Yao H, Brill LM, Han J, Lau E, Bowtell D, Haddad GG, Kaufman RJ and Ronai ZA.  Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2.  PLoS Genet. 2014; 10: e1004348.                                                                         
  9. Douglas RM, Chen AH, Iniguez A, Wang J, Fu ZX, Powell FL, Haddad GG and Yao H. Chemokine receptor-like 2 is involved in ischemic brain injury.  J Exp Stroke Transl Med. 2013 Feb 17; 6:1-6.
  10. Felfly H, Muotri A, Yao H and Haddad GG. Hematopoietic Stem Cell Transplantation Protects Mice from Lethal Stroke. Exp Neurol. 2010; 225:284-93.
  11. Sun XL, Yao H, Douglas RM, Gu XQ, Wang J and Haddad GG. Insulin/PI3K signaling protects dentate neurons from oxygen-glucose deprivation in organotypic slice cultures. J Neurochem. 2010; 112: 377-88
  12. Yao H, Felfly H, Wang J, Zhou D and Haddad GG. DIDS protects against neuronal injury by blockingToll-like receptor 2 activated-mechanisms. J Neurochem. 2009; 108: 835-46.
  13. Xue J, Zhou D, Yao H and Haddad GG. Role of Transporters and Ion Channels in Neuronal Injury under Hypoxia. Am J Physiol Regul Integr Comp Physiol. 2008; R451-457.
  14. Sun XL, Yao H, Zhou D, Gu XQ and Haddad GG. Modulation of hSlo BK current inactivation by fatty acid esters of coenzyme A. J Neurochem. 2008; 104, 1394-1403.
  15. Yao H, Sun XL, Gu XQ, Wang J and Haddad GG. Cell death in an ischemic infarct rim model. J Neurochem. 2007; 103, 1644-1653.
  16. Xue J, Zhou D, Yao H, Gavrialov O, McConnell MJ, Gelb BD and Haddad GG. Novel functional interaction between Na+/H+ exchanger 1 and tyrosine phosphatase SHP-2. Am J Physiol Regul Integr Comp Physiol. 2007; 292, R2406-2416.
  17. Gu XQ, Kanaan A, Yao H and Haddad GG. Chronic high inspired CO2 decreases excitability of mouse hippocampal neurons. J Neurophysiol. 2007; 97, 1833-1838.
  18. Yao H, Shu Y, Wang J, Brinkman BC and Haddad GG. Factors influencing cell fate in the infarct rim. J Neurochem. 2007; 100, 1224-1233.
  19. Yao H and Haddad GG. Calcium and pH homeostasis in neurons during hypoxia and ischemia. Cell Calcium. 2004; 36:247-55
  20. Yao H, Gu XQ and Haddad GG. The role of HCO3--dependent mechanisms in pHi regulation during O2 deprivation. Neurosci. 2003; 117:29-35
  21. Yao H, Donnelly DF, Ma C and LaMotte RH. Up-regulation of hyperpolarization-activated (Ih) current in chronically compressed DRG neurons.  J Neurosci. 2003; 23:2069-74.
  22. Xia Y, Zhao P, Xue J, Gu XQ, Sun X, Yao H and Haddad GG. Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse. J Neurophysiol. 2003; 89:229-36.
  23. Ma C, Shu Y, Zheng Z, Chen Y, Yao H, White FA and LaMotte RH. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol. 2003; 89:1588-602.
  24. Yao H, Gu XQ and Haddad GG. Role of Na+/H+ exchanger during O2 deprivation in mouse CA1 neurons. Am J Physiol Cell Physiol. 2001;  281: C1205-10
  25. Gu XQ, Yao H and Haddad GG. Increased neuronal excitability and seizures in the Na+/H+ exchanger null mutant mouse. Am J Physiol. 2001; 281: C496-503
  26. Gu XQ, Yao H and Haddad GG. Effect of Extracellular HCO3- on Na+ Channel Characteristics in Hippocampal CA1 Neurons. J Neurophysiol. 2000; 84: 2477-83
  27. Yao H, Ma E, Gu XQ and Haddad GG. Intracellular pH regulation of CA1 neurons in Na+/H+ isoform 1 mutant mice. J Clin Invest. 1999; 104:637-45

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