The advent of induced pluripotent stem cell (iPSC) technology has provided a new approach to the establishment of human cell-based models for studying the pathogenesis of neurodevelopmental and neurodegenerative diseases. We have generated human iPSCs directly from patients and differentiated them to patients’ own brain cells. We then further develop 2-dimensional (2D) stem cell neural differentiation models, 3D cerebral organoid models, as well as in vivo human-mouse chimeric brain models to study the disease mechanisms and develop novel therapeutics (Figure 1).

Figure 1
I) Down syndrome (DS), aging, and Alzheimer’s disease (AD). DS is the most common genetic origin of intellectual disability and is the single most common risk factor for early-onset AD. Also called Trisomy 21, this condition occurs when an individual has 3 copies of human chromosome 21 (Hsa21). The additional genetic material causes impairment in cognitive ability and physical growth and is often associated with other complications ranging from cardiac defects to hearing and vision problems. Most physical symptoms of DS can now be treated or alleviated, but there are no effective treatments that improve cognitive function. By the age of 40, people with DS will reliably develop amyloid plaques and neurofibrillary tangles, two pathological hallmarks of AD in the general population and the vast majority will develop AD dementia by their 60s. Therefore, understanding the molecular mechanisms underlying the abnormal brain development and early-onset AD in DS may assist with the development of novel treatments for intellectual disability and AD in this important population as well as for AD in general population.
Representative publications (* co-corresponding author):
Jin M*, Ma Z, Jiang P*. Generation of iPSC-based human-mouse microglial brain chimeras to study senescence of human microglia. STAR Protoc. 2022 Dec 16;3(4):101847.
Jin M, Alam MM, Liu AY, Jiang P. Rag2-/- accelerates lipofuscin accumulation in the brain: Implications for human stem cell brain transplantation studies. Stem Cell Reports. 2022 Nov 8;17(11):2381-2391. doi: 10.1016/j.stemcr.2022.09.012.PubMed PMID: 36270284.
Jin M, Xu R, Wang L, Alam MM, Ma Z, Zhu S, Martini AC, Jadali A, Bernabucci M, Xie P, Kwan KY, Pang ZP, Head E, Liu Y, Hart RP, Jiang P. Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease. Cell Stem Cell. 2022;29(7):1135-53 e8. Epub 2022/07/09. doi: 10.1016/j.stem.2022.06.007. PubMed PMID: 35803230.
Commentary: Kiral FR, Park IH. Human Down syndrome microglia are up for a synaptic feast. Cell Stem Cell. 2022;29(7):1007-8. Epub 2022/07/09. doi: 10.1016/j.stem.2022.06.008. PubMed PMID: 35803219.
Rutgers Today news report: Rutgers Scientists Reveal New Evidence of Key Mechanism in Alzheimer’s
Jiang P, Alam MM. Rise of the human-mouse chimeric brain models. Cell Regeneration. 2022 Sep 3;11(1):32. doi: 10.1186/s13619-022-00135-6. PMID: 36056167

Xu R*, Boreland AJ, Li X, Erickson C, Jin M, Atkins C, Pang ZP, Daniels BP, Jiang P*. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. Stem Cell Reports, 2021 Aug 10; 16(8):1923-1937

Kim H* and Jiang P*. Generation of Human Pluripotent Stem Cell-Derived Fused Organoids with Oligodendroglia and Myelin. STAR Protocols. 2021 Apr 7;2(2):100443.

Jiang, P., Turkalj, L., & Xu, R. High-Fidelity Modeling of Human Microglia with Pluripotent Stem Cells. Cell Stem Cell, 2020. May 7; 26, 629-631.

Xu R, Li X, Boreland AJ, Posyton A, Kwan K, Hart RP, Jiang P.  Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain. Nat Commun. 2020 Mar 27;11(1):1577.
Xu, R., Brawner, A. T., Li, S., Liu, J. J., Kim, H., Xue, H., Pang, Z. P., Kim, W. Y., Hart, R. P., Liu, Y., & Jiang, P. OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome. Cell Stem Cell. 2019 Jun 6;24(6):908-926.e8.
Commentary: Manley WF, Anderson. SA. Dosage Counts: Correcting Trisomy-21-Related Phenotypes in Human Organoids and Xenografts. Cell Stem Cell. 2019 Jun 6;24(6):835-836.
Commentary: Ming Yang. A bit too much Olig2 in Down’s syndrome. Science Translational Medicine 05 Jun 2019: Vol. 11, Issue 495, eaay1425
Rutgers Today news report: Targeting Key Gene Could Help Lead to Down Syndrome Treatment

Kim, H., Xu, R., Padmashri, R., Dunaevsky, A., Liu, Y., Dreyfus, C. F., & Jiang, P. Pluripotent Stem Cell-Derived Cerebral Organoids Reveal Human Oligodendrogenesis with Dorsal and Ventral Origins. Stem Cell Reports, 2019 May 12, 890-905.

Chen C, Kim W, Jiang P. Humanized Neuronal Chimeric Mouse Brain Generated by Neonatally Engrafted Human iPSC-Derived Primitive Neural Progenitor Cells. Journal of Clinical Investigation Insight. 2016 Nov 1(19):e88632.