- Ph.D. — University of Pennsylvania
- M.S. — University of Science and Technology of China
- B.A. — Chinese Pharmaceutical University
- Graduate Faculty, Burnett School of Biomedical Sciences
Development of in vitro human neurobiological models by utilizing human stem cells, especially human induced pluripotent stem cell (iPSC) technology; investigation of neurological diseases by developing iPSC-derived disease models; development of human-on-a-chip systems for preclinical drug discovery and toxicology investigations with the integration of multidisciplinary technologies.
Examples of Research Undergoing
I. IPSC-derived neuromuscular junction (NMJ) system for NMJ diseases such as ALS (Figure 1). We have developed protocols for reliably differentiating motoneurons and skeletal muscle cells from human iPSCs as well as their co-cultures. By integrating the Bio-MEMs technology, a functional NMJ system was developed by adapting the co-culture into a dual-chamber system in which the high content NMJ function can be monitored non-invasively. Application of the cell differentiation protocol to the ALS patients’ iPSC lines allows the investigation of the ALS pathology at the cellular level. Integration of patient iPSC-derived motoneurons and muscle cells into the NMJ platform generated the patient-specific NMJ model in a dish that provides functional readouts simulating clinical observations. IPSC-derived motoneurons and skeletal muscle cells, as well as the developed NMJ platform have been utilized extensively in modeling relevant diseases, including ALS, Myasthenia Gravis and a rare neuromuscular disorder, congenital NGLY1 deficiency. This NMJ system is also applied to the investigation of peripheral pathogenesis of Alzheimer’s disease (AD).
II. IPSC-derived cortical neural tri-culture system to investigate neuron-glia interactions in AD pathogenesis. A tri-culture system was developed consisting of cortical neurons, astrocytes and microglia. The protocols were established for differentiating all three types of cells from iPSCs, and the development of the tri-culture system. Currently, this tri-culture platform is utilized for AD pathogenesis study by introducing AD patient-derived cells.
III. IPSC-PreBӧtC neurons and opioid overdose model. A de novo protocol was developed for differentiating preBӧtC-like neurons from iPSC. These neurons are in charge of inspiration rhythmicity and are one of the major targets of opioid overdose that causes overdose-induced-respiration depression (OIRD) and death. This iPSC-preBӧtC-based opioid overdose model has now been integrated into a microphysiological system (MPS) for the evaluation of drug toxicity.
IV. Investigation of the pathophysiology of human muscle diseases utilizing human iPSC-skeletal muscle. A study on sarcopenia induced by hyperglycemia demonstrated that hyperglycemia reduced muscle regeneration capability, deformed myofiber structure, impaired muscle function, and caused premature cell death. These findings provided insight about diabetes pathology and the hazard of gestational diabetes. This platform will be utilized for further disease investigations and therapeutic development.
Ongoing and recently completed projects
- NIH/NIA: Investigation of the role of glia cells in Alzheimer’s pathogenesis in a functional human-based in vitro model. 1/15/2021 – 12/31/2023 (PI)
- LIFE Gerontology Research Awards at UCF: Investigation of hyperglycemia-induced sarcopenia in a human-based functional system. 4/1/2018 – 4/1/2022 (PI)
- Hesperos/NIH: Modulatory Role of Blood-Brain-Barrier and Enzymatic Activity in an Innovative Human Model of Cholinergic Drug Induced Dementia. 2/1/2022 – 7/31/2023 (PI)
- NIH/NCATS: Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity. 9/27/2019 – 7/31/2024 (Co-PI, with Dr. Hickman as the PI)
- NIH: Investigating the role of Alzheimer’s disease familial mutations in neuromuscular physiology, 4/1/2022 – 3/31/2027 (Co-PI, with Dr. Hickman as the PI)
- NIH/NINDS: An In Vitro Model of Stem Cell Innervation of Myotubes. 9/01/2016 – 5/31/2022 (Co-PI, with Dr. Hickman as the PI)
Patents & Publications
Badu-Mensah, X. Guo, S. Nimbalkar, Y. Cai, J.J. Hickman. ALS mutations in both human skeletal muscle and motoneurons differentially affects neuromuscular junction integrity and function. Biomaterials. 2022, 289:121752.
Agnes Badu-Mensah, Paola Valinski, Hemant Parsaud, James J Hickman, Xiufang Guo. Hyperglycemia negatively affects IPSC-derived myoblast proliferation and skeletal muscle regeneration and function. Cells 2022, 11:03674.
Sasserath T, Robertson AL, Mendez R, Hays TT, Smith E, Cooper H, Akanda N, Rumsey JW, Guo X, Farkhondeh A, Pradhan A, Baumgaertel K, Might M, Rodems S, Zheng W, and Hickman JJ. An induced pluripotent stem cell-derived NMJ platform for study of the NGLY1-congenital disorder of deglycosylation. Advanced Therapeutics. 2022; 5(11): 2200009.
Autar K, Guo X, Rumsey JW, Long C, Akanda N, Jackson M, Narasimhan NS, Caneus J, Morgan D, Hickman JJ. Establishment of an hiPSC-cortical neuron differentiation and maturation model and its application to neurological disorders through human body-on-a-chip systems. Stem Cell Report. 2022;17(1): 96-109.
Badu-Mensah, A., X. Guo, J.J. Hickman. (2021). ALS Skeletal Muscle: Victim or culprit. The Neuroscience Chronicles. 2021;2(2):31-33.
Guo X, Badu-Mensah A, Thomas MC, McAleer CW, Hickman JJ. Characterization of functional human skeletal myotubes and neuromuscular junction derived from the same induced pluripotent stem cell source. Bioengineering (Basel). 2020 Oct 22;7(4).
Badu-Mensah A, Guo X, McAleer CW, Rumsey JW, Hickman JJ. Functional skeletal muscle model derived from SOD1-mutant ALS patient iPSCs recapitulates hallmarks of disease progression. Sci Rep. 2020 Aug 31;10(1):14302.
Caneus J, Akanda N, Rumsey JW, Guo X, Jackson M, Long CJ, Sommerhage F, Georgieva S, Kanaan NM, Morgan D, Hickman JJ. A human induced pluripotent stem cell-derived cortical neuron human-on-a chip system to study Aβ42 and tau-induced pathophysiological effects on long-term potentiation. Alzheimer’s Dement (N Y). 2020;6(1):e12029.
Colón A, Badu-Mensah A, Guo X, Goswami A, Hickman JJ. Differentiation of intrafusal fibers from human induced pluripotent stem cells. ACS Chem Neurosci. 2020 Apr 1;11(7):1085-1092.
Guo X, Smith V, Jackson M, Tran M, Thomas M, Patel A, Lorusso E, Nimbalkar S, Cai Y, Christopher W. McAleer CW, Ying Wang Y, Long CJ, Hickman JJ. A Human‐based functional NMJ system for personalized ALS modeling and drug testing. Advanced Therapy. 2020; 3:2000133.
LoRusso E, Hickman JJ, Guo X. Ion channel dysfunction and altered motoneuron excitability in ALS. Neurol Disord Epilepsy J. 2019;3(2).
Gonzalez M, Guo X, Lin M, Stancescu M, Molnar P, Spradling S, Hickman JJ. Polarity induced in human stem cell derived motoneurons on patterned self-assembled monolayers. ACS Chem Neurosci. 2019 Jun 19;10(6):2756-2764. (Equal contribution)
Patrón LA, Nagatomo K, Eves DT, Imad M, Young K, Torvund M, Guo X, Rogers GC, Zinsmaier KE. Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity. J Cell Biol. 2019 Mar 4;218(3):993-1010.
Simandi Z, Pajer K, Karolyi K, Sieler T, Jiang LL, Kolostyak Z, Sari Z, Fekecs Z, Pap A, Patsalos A, Contreras GA, Reho B, Papp Z, Guo X, Horvath A, Kiss G, Keresztessy Z, Vámosi G, Hickman J, Xu H, Dormann D, Hortobagyi T, Antal M, Nógrádi A, Nagy L. Arginine methyltransferase PRMT8 provides cellular Stress tolerance in aging motoneurons. J Neurosci. 2018 Aug 29;38(35):7683-7700.
Santhanam N, Kumanchik L, Guo X, Sommerhage F, Cai Y, Jackson M, Martin C, Saad G, McAleer CW, Wang Y, Lavado A, Long CJ, Hickman JJ. Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics. Biomaterials. 2018 Jun;166:64-78. (Equal contribution)
Lavado A, Guo X, Smith AS, Akanda N, Martin C, Cai Y, Elbrecht D, Tran M, Bryant JP, Colon A, Long CJ, Lambert S, Morgan D, Hickman JJ. Evaluation of holistic treatment for ALS reveals possible mechanism and therapeutic potential. Int J Pharm Pharm Res. 2017 Dec;11(1):348-374. (Equal contribution)
Colón A, Guo X, Akanda N, Cai Y, Hickman JJ. Functional analysis of human intrafusal fiber innervation by human γ-motoneurons. Sci Rep. 2017 Dec 8;7(1):17202.
Guo X, Colon A, Akanda N, Spradling S, Stancescu M, Martin C, Hickman JJ. Tissue engineering the mechanosensory circuit of the stretch reflex arc with human stem cells: Sensory neuron innervation of intrafusal muscle fibers. Biomaterials. 2017 Apr;122:179-187.
Oleaga C, Bernabini C, Smith AS, Srinivasan B, Jackson M, McLamb W, Platt V, Bridges R, Cai Y, Santhanam N, Berry B, Najjar S, Akanda N, Guo X, Martin C, Ekman G, Esch MB, Langer J, Ouedraogo G, Cotovio J, Breton L, Shuler ML, Hickman JJ. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep. 2016 Feb 3;6:20030.
Berry BJ, Akanda N, Smith AS, Long CJ, Schnepper MT, Guo X, Hickman JJ. Morphological and functional characterization of human induced pluripotent stem cell-derived neurons (iCell Neurons) in defined culture systems. Biotechnol Prog. 2015 Nov-Dec;31(6):1613-22.
Guo X, Greene K, Akanda N, Smith A, Stancescu M, Lambert S, Vandenburgh H, Hickman J. In vitro Differentiation of Functional Human Skeletal Myotubes in a Defined System. Biomater Sci. 2014 Jan 1;2(1):131-138.
Guo X, Spradling S, Stancescu M, Lambert S, Hickman JJ. Derivation of sensory neurons and neural crest stem cells from human neural progenitor hNP1. Biomaterials. 2013 Jun;34(18):4418-27.
Guo X, Ayala JE, Gonzalez M, Stancescu M, Lambert S, Hickman JJ. Tissue engineering the monosynaptic circuit of the stretch reflex arc with co-culture of embryonic motoneurons and proprioceptive sensory neurons. Biomaterials. 2012 Aug;33(23):5723-31.
Davis H, Guo X, Lambert S, Stancescu M, Hickman JJ. Small Molecule Induction of Human Umbilical Stem Cells into MBP-positive Oligodendrocytes in a Defined Three-Dimensional Environment. ACS Chem Neurosci. 2012 Jan 18;3(1):31-39.
Guo X, Gonzalez M, Stancescu M, Vandenburgh HH, Hickman JJ. Neuromuscular junction formation between human stem cell-derived motoneurons and human skeletal muscle in a defined system. Biomaterials. 2011 Dec;32(36):9602-11.
Guo X, Das M, Rumsey J, Gonzalez M, Stancescu M, Hickman J. Neuromuscular junction formation between human stem-cell-derived motoneurons and rat skeletal muscle in a defined system. Tissue Eng Part C Methods. 2010 Dec;16(6):1347-55.
Guo X, Johe K, Molnar P, Davis H, Hickman J. Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J Tissue Eng Regen Med. 2010 Mar;4(3):181-93.
Das M, Rumsey JW, Gregory CA, Bhargava N, Kang JF, Molnar P, Riedel L, Guo X, Hickman JJ. Embryonic motoneuron-skeletal muscle co-culture in a defined system. Neuroscience. 2007 May 11;146(2):481-8.
Guo X, Macleod GT, Wellington A, Hu F, Panchumarthi S, Schoenfield M, Marin L, Charlton MP, Atwood HL, Zinsmaier KE. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron. 2005 Aug 4;47(3):379-93.
Bronk P, Wenniger JJ, Dawson-Scully K, Guo X, Hong S, Atwood HL, Zinsmaier KE. Drosophila Hsc70-4 is critical for neurotransmitter exocytosis in vivo. Neuron. 2001 May;30(2):475-88.
Guo X., F. Sommerhage, C. McAleer, C. Martin, C. Long, Y. Wang, N. Santhanam, A. Colon, C. Oleaga Sancho, J. J. Hickman. “In vitro Modeling of Nervous System- Engineering of the Reflex Arc” in Neural Engineering. Editor: L.G. Zhang, D.L. Kaplan. Springer International Publishing, Switzerland 2016
Smith A.S.T., C.J. Long, C. McAleer, X. Guo, M. Esch, J.M. Prot, M. Shuler and J.J. Hickman “Body-on-a-Chip” Technology and Supporting Microfluidics. In: Human-Based Systems for Translational Research. Editor, R. Coleman. Royal Society of Chemistry. 2014
Guo X., J.J. Hickman. “Treatment of ALS utilizing a stem cell strategy” in Motor Neuron Diseases: Causes, Classification and Treatments, Nova Science Publishers, Hauppauge, New York. 2011.
X. Guo, M. Stancescu, M. Gonzales, J.J. Hickman, “Formation of neuromuscular junction in a co-culture comprising rat muscle cells overlayered with differentiated human spinal cord stem cells in a serum free medium,” U.S. Patent No. 9,952,204, April 24, 2018.
X. Guo and J.J. Hickman, “A Synthetic Mammalian Neuromuscular Junction and Method of Making,” U.S. Patent No. 9,267,936 B2, Feb. 23, 2016.
X. Guo and J.J. Hickman, “Formation of Neuromuscular Junctions in a Defined System,” CA Patent Application Number 2,798,777, September 6, 2016.
X. Guo and J.J. Hickman, “Nociceptor-Like Cells Differentiated from Human Neural Progenitors and Uses Thereof” U.S. Non-Provisional Patent Application No. 15/235,867, filed on 8/12/2016.