Publications by authors named "Jinghua Piao"

8 Publications

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Biphasic Activation of WNT Signaling Facilitates the Derivation of Midbrain Dopamine Neurons from hESCs for Translational Use.

Cell Stem Cell 2021 Feb;28(2):343-355.e5

Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Human pluripotent stem cells show considerable promise for applications in regenerative medicine, including the development of cell replacement paradigms for the treatment of Parkinson's disease. Protocols have been developed to generate authentic midbrain dopamine (mDA) neurons capable of reversing dopamine-related deficits in animal models of Parkinson's disease. However, the generation of mDA neurons at clinical scale suitable for human application remains an important challenge. Here, we present an mDA neuron derivation protocol based on a two-step WNT signaling activation strategy that improves expression of midbrain markers, such as Engrailed-1 (EN1), while minimizing expression of contaminating posterior (hindbrain) and anterior (diencephalic) lineage markers. The resulting neurons exhibit molecular, biochemical, and electrophysiological properties of mDA neurons. Cryopreserved mDA neuron precursors can be successfully transplanted into 6-hydroxydopamine (6OHDA) lesioned rats to induce recovery of amphetamine-induced rotation behavior. The protocol presented here is the basis for clinical-grade mDA neuron production and preclinical safety and efficacy studies.
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http://dx.doi.org/10.1016/j.stem.2021.01.005DOI Listing
February 2021

Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01.

Cell Stem Cell 2021 Feb;28(2):217-229.e7

Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra leading to disabling deficits. Dopamine neuron grafts may provide a significant therapeutic advance over current therapies. We have generated midbrain dopamine neurons from human embryonic stem cells and manufactured large-scale cryopreserved dopamine progenitors for clinical use. After optimizing cell survival and phenotypes in short-term studies, the cell product, MSK-DA01, was subjected to an extensive set of biodistribution, toxicity, and tumorigenicity assessments in mice under GLP conditions. A large-scale efficacy study was also performed in rats with the same lot of cells intended for potential human use and demonstrated survival of the grafted cells and behavioral amelioration in 6-hydroxydopamine lesioned rats. There were no adverse effects attributable to the grafted cells, no obvious distribution outside the brain, and no cell overgrowth or tumor formation, thus paving the way for a future clinical trial.
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http://dx.doi.org/10.1016/j.stem.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903922PMC
February 2021

Long-term clinically relevant rodent model of methotrexate-induced cognitive impairment.

Neuro Oncol 2020 08;22(8):1126-1137

Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: With the enhanced use of chemotherapy and the advent of increased patient survival rates, there are an increasing number of cancer survivors living with chemotherapy-induced cognitive impairment. A growing number of clinical studies have brought to light the association of agents like methotrexate in generating these neurological sequelae, although mechanisms remain unclear.

Methods: Here, we use a clinically relevant regimen of several cycles of methotrexate and leucovorin rescue to develop a model of chemotherapy-induced cognitive impairment, and investigate the in vivo long-term (16 mo) impact of high-dose systemic methotrexate on white matter cellular dynamics as assessed by stereology, animal behavior, and diffusion tensor imaging.

Results: Our results indicate that at 6 and 16 months post-chemotherapy, methotrexate-treated rats exhibit a significant and permanent decrease in the number of oligodendrocytes and their progenitors in the white matter, in corpus callosum volumes, and myelin basic protein. These findings are associated with mostly delayed deficits in performance on Morris Water Maze and Novel Object Recognition tasks. Diffusion tensor imaging demonstrates significantly decreased fractional anisotropy values in the callosum genu, body, and splenium, as well as previously unassessed areas like the fimbria. Interestingly, these white matter changes are preceded by an earlier, transient decrement in white matter microglia at 3 months, and hippocampal neural progenitors at 3 and 6 months.

Conclusion: These results demonstrate a significant negative impact of methotrexate on the oligodendrocyte compartment and white matter, associated with cognitive impairment. The data also support the use of diffusion tensor imaging in monitoring white matter integrity in this context.
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http://dx.doi.org/10.1093/neuonc/noaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594568PMC
August 2020

Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells.

Stem Cell Reports 2016 06;6(6):858-872

The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

Human pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.
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http://dx.doi.org/10.1016/j.stemcr.2016.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912387PMC
June 2016

Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation.

Cell Stem Cell 2015 Feb;16(2):198-210

Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Electronic address:

Radiation therapy to the brain is a powerful tool in the management of many cancers, but it is associated with significant and irreversible long-term side effects, including cognitive decline and impairment of motor coordination. Depletion of oligodendrocyte progenitors and demyelination are major pathological features that are particularly pronounced in younger individuals and severely limit therapeutic options. Here we tested whether human ESC-derived oligodendrocytes can functionally remyelinate the irradiated brain using a rat model. We demonstrate the efficient derivation and prospective isolation of human oligodendrocyte progenitors, which, upon transplantation, migrate throughout the major white matter tracts resulting in both structural and functional repair. Behavioral testing showed complete recovery of cognitive function while additional recovery from motor deficits required concomitant transplantation into the cerebellum. The ability to repair radiation-induced damage to the brain could dramatically improve the outlook for cancer survivors and enable more effective use of radiation therapies, especially in children.
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http://dx.doi.org/10.1016/j.stem.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425211PMC
February 2015

Neuroprotective effects of human spinal cord-derived neural precursor cells after transplantation to the injured spinal cord.

Exp Neurol 2014 Mar 8;253:138-45. Epub 2014 Jan 8.

Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Geriatric Clinic Res Lab., Novum, S-14186 Stockholm, Sweden; Stockholms Sjukhem Foundation, Mariebergsgatan 22, S-11235 Stockholm, Sweden. Electronic address:

To validate human neural precursor cells (NPCs) as potential donor cells for transplantation therapy after spinal cord injury (SCI), we investigated the effect of NPCs, transplanted as neurospheres, in two different rat SCI models. Human spinal cord-derived NPCs (SC-NPCs) transplanted 9 days after spinal contusion injury enhanced hindlimb recovery, assessed by the BBB locomotor test. In spinal compression injuries, SC-NPCs transplanted immediately or after 1 week, but not 7 weeks after injury, significantly improved hindlimb recovery compared to controls. We could not detect signs of mechanical allodynia in transplanted rats. Four months after transplantation, we found more human cells in the host spinal cord than were transplanted, irrespective of the time of transplantation. There was no focal tumor growth. In all groups the vast majority of NPCs differentiated into astrocytes. Importantly, the number of surviving rat spinal cord neurons was highest in groups transplanted acutely and subacutely, which also showed the best hindlimb function. This suggests that transplanted SC-NPCs improve the functional outcome by a neuroprotective effect. We conclude that SC-NPCs reliably enhance the functional outcome after SCI if transplanted acutely or subacutely, without causing allodynia. This therapeutic effect is mainly the consequence of a neuroprotective effect of the SC-NPCs.
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http://dx.doi.org/10.1016/j.expneurol.2013.12.022DOI Listing
March 2014

Specification of functional cranial placode derivatives from human pluripotent stem cells.

Cell Rep 2013 Dec 27;5(5):1387-402. Epub 2013 Nov 27.

Center for Stem Cell Biology, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA; Department of Neurosurgery, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA. Electronic address:

Cranial placodes are embryonic structures essential for sensory and endocrine organ development. Human placode development has remained largely inaccessible despite the serious medical conditions caused by the dysfunction of placode-derived tissues. Here, we demonstrate the efficient derivation of cranial placodes from human pluripotent stem cells. Timed removal of the BMP inhibitor Noggin, a component of the dual-SMAD inhibition strategy of neural induction, triggers placode induction at the expense of CNS fates. Concomitant inhibition of fibroblast growth factor signaling disrupts placode derivation and induces surface ectoderm. Further fate specification at the preplacode stage enables the selective generation of placode-derived trigeminal ganglia capable of in vivo engraftment, mature lens fibers, and anterior pituitary hormone-producing cells that upon transplantation produce human growth hormone and adrenocorticotropic hormone in vivo. Our results establish a powerful experimental platform to study human cranial placode development and set the stage for the development of human cell-based therapies in sensory and endocrine disease.
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http://dx.doi.org/10.1016/j.celrep.2013.10.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887225PMC
December 2013

Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.

Nature 2011 Nov 6;480(7378):547-51. Epub 2011 Nov 6.

Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.
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http://dx.doi.org/10.1038/nature10648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245796PMC
November 2011