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Generation of Functional Human 3D Cortico-Motor Assembloids
Open accessAbstract
SUMMARY Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10 weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.
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TL;DR
The paper generates three-dimensional human cortico-motor assembloids by fusing hiPS cell-derived cortical spheroids, hindbrain/cervical spinal cord spheroids, and skeletal muscle spheroids. It shows that cortical neurons connect to spinal spheroids, spinal motor neurons connect to muscle, and cortical stimulation can drive muscle contraction in vitro for up to 10 weeks.
Key findings
- hSpS resembling hindbrain/cervical spinal cord were generated from hiPS cells; condition 8 (0.1 µM RA, 0.1 µM SAG, 10 ng/mL FGF-2) was selected, and DAPT exposure produced a ~3-fold increase in motor neurons and a 4-fold decrease in an undefined mixed neuronal population. Single-cell profiling included n = 7,888 cells (BD Rhapsody) and n = 9,302 cells across three hiPS cell lines (10x Genomics).
- In hCS-hSpS assembloids, hCS-derived eYFP projections increased over time; rabies tracing showed ~95% of GFP+/mCherry+ hCS cells co-expressed MAP2, <4% GFAP, ~60% CTIP2, and ~12% BRN2. Optogenetic stimulation of hCS elicited calcium spikes in hSpS in 4/10 assembloids, with median response amplitude ~5 times higher than random time points (n = 16 cells, p = 0.0005), blocked by NBQX/APV; patch-clamp found reliable postsynaptic currents in 2/30 recorded Hb9+ cells across 4 assembloids.
- In hSpS-hSkM assembloids, rabies tracing showed 90% of GFP+ cells were CHAT+, <5% GABA+, and ~45% ISL1+; glutamate uncaging caused muscle contraction that was blocked by curare. In hCS-hSpS-hSkM assembloids, spontaneous contractions were ~5× more frequent than hSkM alone or hCS-hSkM, and optogenetic hCS stimulation induced global contractions in 85.7% of tested assembloids and 40% of pulses, abolished by NBQX/APV.
- Assembloids remained morphologically and functionally intact for up to 10 weeks; optogenetic contraction success was 50% at 8 weeks versus 81% at 5 weeks (p = 0.06), while calcium responses after 5 stimulations were more robust at 7–8 weeks (p = 0.003 for Stim 5).
Methods
- Used n = 9 hiPS cell lines from 8 healthy subjects to generate human cortical spheroids (hCS), hindbrain/cervical spinal cord spheroids (hSpS), human skeletal myoblasts (hSkM), and hiPS cell-derived myoblasts (ihSkM); assembled hCS-hSpS, hSpS-hSkM, and hCS-hSpS-hSkM cultures, plus mouse E11.5 limb bud co-cultures.
- Characterized cells and circuits with single-cell transcriptomics (BD Rhapsody and 10x Genomics), qPCR, immunocytochemistry, electron microscopy, rabies tracing, calcium imaging, patch-clamp electrophysiology, optogenetics, glutamate uncaging, and MUSCLEMOTION contraction analysis.
- Statistical comparisons are reported throughout using p-values from the described assays; sample sizes and cell-line/differentiation details are in Table S1 and figure legends.
Limitations
- The paper states that further improvements are needed: more caudal spinal cord cell types, organizing centers or other strategies to improve progenitor domain organization, assessment of ascending projections, and optimization of optogenetics with cell-type-specific reporters.
- The text also notes that direct comparison to human developing hindbrain/spinal cord in the future could better address identity questions; rabies infection of 3D hSkM was challenging, yielding fewer GFP+ cells in some assembloids; and optogenetic success depends on light-pulse duration and opsin delivery efficiency.
- Evident from the reported results: only 4/10 assembloids showed calcium responses in hCS-hSpS, only 2/30 recorded Hb9+ cells showed reliable postsynaptic currents, one hiPS cell line had a higher proportion of V2a neurons at the expense of motor neurons, and the hSpS single-cell analysis did not identify a clear V3 domain or non-ectodermal cells.
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69 Own result · 22 Not checked yet · 16 Own method · 13 Own interpretation · 2 No basis given
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“we find that human-induced pluripotent stem (hiPS) cell-derived region-specific spheroids form physiologically relevant connections when assembled together”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
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“exposure to low levels of RA and high levels of FGF-2 yields more caudal fates (Figure S1D; HOXC9, p = 0.002)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“high SAG exposure is associated with higher expression of ventral marker genes (Figures S1E and S1F; OLIG2, p = 0.001; NKX6–1, p = 0.002; CHX10, p = 0.007; and ISL1, p = 0.01)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“We first generated spheroids resembling the human hindbrain/cervical spinal cord (hSpS) starting from hiPS cells”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“Exposure to high levels of RA and low levels of FGF-2 results in more rostral fates (Figure S1D; HOXA2, p = 0.002)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“assembloids at 8 weeks tended to be more likely to repeatedly contract following five consecutive stimulations (Figures 7M and 7N; p = 0.06)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
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“Further quantification showed that ~45% of these cells were also positive for the motor neuron-related transcription factor ISL1 but not for CHX10, PROX1, or FOXP2”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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“Immunocytochemistry of hSkM after co-culture with hSpS revealed binding of bungarotoxin (BTX)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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“We found that neurons in hSpS in 4 out of 10 assembloids responded with calcium spikes that followed the stimulus after ~200 ms”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Viral Tracing, Optogenetics, and Calcium Imaging in Cortico-Spinal Assembloids
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“by 12 daf hSpS sent out abundant projections to the 3D hSkM”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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“found that ~40% of OLIG2+ cells co-expressed the marker NKX2.2 and ~15% co-expressed NKX6.1”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“Spheroids resembling the cerebral cortex form long-range functional connections with spheroids resembling the hindbrain/cervical spinal cord, and these in turn project and connect with human skeletal muscle.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
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“We found that OLIG2 was more highly expressed toward the edge of the hSpS, whereas PAX6 showed the opposite pattern, with higher expression toward the center”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“In condition 8 (hSpS), the neuroectodermal markers SOX1 and PAX6 peaked at day 10, followed by an increase in the expression of OLIG2 and NKX6–1 from day 12”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“Activity in hSpS-limb assembloids persisted for at least 2 weeks in vitro and was completely blocked by addition of the acetylcholine receptor antagonist curare (100 µM; χ2 test, p = 0.02”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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“we found that the proportion of active hSkM doubled in hSpS-hSkM in comparison to hSkM in isolation or co-cultured with hCS (hSpS-hSkM versus hSkM p = 0.01; Figures 5E and S6D; Video S2, sequence 2). This effect was observed mainly in hSkM within 1 mm of hSpS (hSkM versus hSpS-hSkM <1 mm, p < 0.0001; Figures S6E and S6F) and was blocked by curare”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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“We did not find a clear V3 domain with this analysis, and we found no non-ectodermal cells, however, we identified a group of neural cells that we could not define based on known marker genes.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“We found that hSkM contracted after light stimulation at both time points, although the success rate for contracting assembloids at 8 weeks tended to be decreased (50% versus 81% success rate at 8 and 5 weeks, respectively; p = 0.06”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
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“Quantification of the eYFP+-covered area in hSpS in intact hCS-hSpS assembloids showed a progressive increase of eYFP over time (5 daf versus 10 daf p = 0.009; 5 daf versus 20 daf p < 0.0001; Figures 3D, S5F, and S5G for examples of hCS-hSpS assembloids at 20 daf), and this was not observed to the same extent in hCS-hCS assembloids”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Cortico-Spinal Assembloids
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“we examined the expression of HOX genes in hSpS and found expression of HOXB4, HOXC4, and HOXB5”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“We found that ~95% of the GFP+/mCherry+ cells in hCS co-expressed the neuronal marker MAP2 and fewer than 4% expressed the glial lineage marker GFAP”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Viral Tracing, Optogenetics, and Calcium Imaging in Cortico-Spinal Assembloids
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“This resulted in robust muscle contraction (p = 0.002) (Figures 6F–6H) suggesting functional assembly of a cortico-spinal-muscle functional unit. The contraction was blocked by treatment with 100 µm curare (Figures 6G, S7D, and S7E) and was not related to UV exposure”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Applications in Cortico-Motor Assembloids
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“limb buds displayed spontaneous contractions when assembled with hSpS, but not when kept in isolation or when assembled with hCS (χ2 test, p = 0.02”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
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- Rests on an assumption: Mouse limb buds dissected at embryonic day 11.5 have not yet received spinal cord axonal innervation.
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In the paper
“We also confirmed the presence of cholinergic motor neurons in hSpS by immunocytochemistry for the enzyme that catalyzes the biosynthesis of the neurotransmitter acetylcholine (CHAT), the vesicular acetylcholine transporter VACHT, the neurofilament SMI-32, and the transcription factors HB9, ISL1, and PHOX2B”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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In the paper
“We found that almost 60% of all GFP+/mCherry+ cells co-expressed the corticofugal marker CTIP2, and only ~12% co-expressed BRN2”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Viral Tracing, Optogenetics, and Calcium Imaging in Cortico-Spinal Assembloids
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“Live imaging at 5 days after fusion (daf) showed processes derived from cells in the hCS extending into hSpS”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Cortico-Spinal Assembloids
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“hSpS cells sometimes projected into hCS but seldom migrated (Figure S5J). Similarly, we did not observe hSpS-derived Hb9 cells migrating into hCS”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Cortico-Spinal Assembloids
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“hSpS cell cluster identity and found they included progenitors expressing SOX9 and TOP2A, astroglia, and several neuronal domains including a dorsal group of cells expressing LHX2, INSM1, ST18, and TLX3”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“We also observed the presence of ventral neuronal domains in hSpS by immunohistochemistry at day 45 (Figures 2E, 2F, and S4G), as well as the presence of astrocytes and oligodendrocytes at day 75”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
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“We observed extensive expression of GFP in hSpS and cells co-expressing GFP and mCherry in hCS”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Viral Tracing, Optogenetics, and Calcium Imaging in Cortico-Spinal Assembloids
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“we found no significant difference in the number of contractions or the covariance between hSpS-hSkM and hCS-hSpS-hSkM (p = >0.99)”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Applications in Cortico-Motor Assembloids
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“we used immunohistochemistry in hCS-hSpS-hSkM assembloids at 10 weeks (Figure 7G) and found the presence of hCS-derived projections into hSpS (Figures 7H and S7U), motor neurons (Figure 7I, S7U, and S7V), non-reactive astrocytes (Figures 7H and S7V), myelinating oligodendrocytes (Figures 7H and 7I) and neuromuscular junctions”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
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“Activation of Chrimson-expressing hCS induced global contractions in hSkM in 85.7% of tested assembloids (p = 0.01) (Figures 6L and 6M; Video S5, sequence 1) and 40% of pulses”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Applications in Cortico-Motor Assembloids
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that assembloids at this time present intact axons and dendrites (Figure S7N), mature synapses (Figures 7B, 7C, S7O, and S7P), organized skeletal muscle fibers (Figures 7D and S7Q), and neuromuscular contacts”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When differentiated in the presence of DAPT, although overall similar to the unexposed condition (hSpS(–)DAPT; R2 = 0.85, p < 0.0001), hSpS contained a ~3-fold increase in the proportion of motor neurons as well as a 4-fold decrease in the proportion of an undefined mixed neuronal population”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
plaindirectn = 7,888- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Activation of Chrim-expressing hCS induced calcium spikes in hSkM fibers (Figures 6Q and 6R; Video S5, sequence 2), and these were dependent on the presence of Chrimson”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Applications in Cortico-Motor Assembloids
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Photostimulation of hSpS in hSpS-hSkM assembloids resulted in robust hSkM contraction in the presence, but not in the absence, of MNI-caged glutamate (Figures 5M, 5N, S6O, and S6P; Video S3), and addition of curare stopped hSkM contractions”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Differentiated myotubes expressed markers of mature skeletal muscle, such as desmin (DES), titin (TTN), and the heavy chain myosin (MyHC), and became multinucleated”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Light-induced hCS activity elicited calcium spikes in hSkM at both 4–5 and 7–8 weeks, but although hSkM fibers in assembloids respond to the first stimulation at both ages, only at the later time point cells are able to maintain a robust response after 5 stimulations”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Gene expression profiles of 4,175 and 3,173 cells were recovered for hSpS with or without DAPT, respectively, with an average number of reads of ~17,000, ~2,400 molecules and ~1,400 number of genes detected per cell with average molecular index coverage (that is, the number of times a molecule was sequenced) of 4.8.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, we showed the generation, from three components, of a functional human neural circuit that contains at least two synaptic contacts.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > DISCUSSION
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Specification of the progenitor domains in the hindbrain and spinal cord relies on signaling molecules like WNT and retinoic acid (RA) secreted along the rostro-caudal axis, and sonic hedgehog (SHH) along the dorso-ventral axis”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent evidence points at primate-specific reorganization and connectivity of the cortico-spinal pathway, including the presence of direct monosynaptic cortico-spinal connections, which may be related to corticalization of motor control and the evolution of dexterity”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Long-range neural projections have been observed in a cortico-thalamic assembloid (Xiang et al., 2019), in organotypic mouse co-cultures (Takuma et al., 2002) and in a preparation that used sliced cortical organoids and rodent spinal cord explants (Giandomenico et al., 2019).”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although components of the cortico-spinal-motor pathway have been generated or studied in isolation (Ogura et al., 2018; Sances et al., 2016; Shi et al., 2018; Steinbeck et al., 2016), the in vitro derivation and assembly of this three-part system have not yet been achieved with human cells.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these cortico-motor assembloids can be used to trace anatomical and functional connectivity, can be maintained long term in vitro to capture cellular and functional changes, and can be manipulated optogenetically or pharmacologically at multiple levels to control human muscle contraction.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Whereas spinal cord progenitors are organized in a well-defined laminar pattern during development, post-mitotic neurons in the spinal cord do not appear to maintain this organization at later stages”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
What the sources say
- Not checked yetcites Lai et al., 2016 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of these cells expressed the motor neuron marker PHOX2B, but did not express the visceral motor neuron marker TBX20, suggesting motor neurons in hSpS have a largely somatic identity”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The balance between V2a interneurons and motor neurons is known to be linked (Thaler et al., 1999), and loss of motor neurons in Olig1/2 knockout mice results in a dramatic increase of Chx10+ V2a interneurons”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
What the sources say
- Not checked yetcites Thaler et al., 1999 source
- Not checked yetcites Zhou and Anderson, 2002
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MN cluster 6 was negative for PHOX2B and positive for ISL1/2 and HB9 (MNX1), indicating a limb-innervating lateral motor column-like identity”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The functional output of the cortico-motor circuit is muscle contraction through motor neuron activity.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Functional Assembly of Spinal Spheroids with Muscle
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some dorsal clusters appeared to be less correlated compared to ventral clusters, which may be explained by the lack of dorsalizing signals in hSpS.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Generation of Hindbrain/Cervical Spinal Cord Spheroids from Pluripotent Stem Cells
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Corticofugal projection neurons, which include cortico-spinal projecting cells, express CTIP2 and are mainly located in deep layers of the cerebral cortex, whereas neurons located in superficial layers express BRN2 and project to the contra-lateral cortex”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Viral Tracing, Optogenetics, and Calcium Imaging in Cortico-Spinal Assembloids
What the sources say
- Not checked yetcites Greig et al., 2013 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells with mitochondrial gene (with a gene symbol starting with MT) content > 30%, were discarded, retaining a total of 7,888 cells from both samples.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Processed gene expression data are available in the Gene Expression Omnibus under accession number GEO: GSE123722.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > RESOURCE AVAILABILITY
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We excluded cells with more than 6,000 or less than 1,000 detected genes, as well as those with a mitochondrial content higher than 18%.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cultures were tested and maintained mycoplasma free.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments in this manuscript were performed with stimulations of 68–100 ms for increased sampling speed and to avoid any light-induced toxicity, yet longer stimulations may yield higher success rates.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Widespread infection of 3D hSkM with rabies-∆G-Cre-eGFP and AAV-8-CAG-FLEX-Rabies G was challenging, which resulted in some assembloids having fewer GFP cells for quantification.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Approval for mouse experiments was obtained from the Stanford University’s Administrative Panel on Laboratory Animal Care (APLAC).”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A total number of 798 (hSkM condition), 652 (hCS + hSkM condition), 1006 (hSpS + hSkM condition) and 727 (hSpS + hSkM + curare condition) hSkM fibers were analyzed.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the proportion of live cells was estimated using a fluorescent assay (~90%) and all cells were used for further processing.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We previously showed the potential of using region-specific spheroids as a modular approach to study human interneuron migration and identify disease phenotypes (Birey et al., 2017).”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > DISCUSSION
What the sources say
- Not checked yetcites Birey et al., 2017 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Approval for using these lines was obtained from the Stanford IRB panel and informed consent was obtained from all subjects.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The hiPS cell lines used in this study were validated using standard methods as previously described (Paşca et al., 2011; Sloan et al., 2018).”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
What the sources say
- Not checked yetcites Paşca et al., 2011
- Not checked yetcites Sloan et al., 2018 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results demonstrate that the assembly of intact 3D human cultures resembling the cerebral cortex, hindbrain/spinal cord and skeletal muscle enables the formation of neural circuits that can be readily manipulated over several weeks in vitro to model cortical control of muscle contraction.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > RESULTS > Long-Term Culture and Functionality of Cortico-Motor Assembloids
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, because low opsin expression may result in reduced stimulation success, inspection of hCS AAV-1-hSYN1-ChrimsonR-tdT expression before assembly is recommended.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Human brain specimens were obtained under a protocol approved by the Research Compliance Office at Stanford University.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that optogenetic stimulation experiments depend on at least two factors: (i) the duration of light pulses, and (ii) the efficiency of opsin delivery.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Validation of hiPS genome integrity was performed by high density SNP arrays.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only assembloids with at least 10 GFP+ cells were included in the analysis.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We excluded genes that were not expressed in at least three cells.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Due to sex differences between hiPS cell lines we also removed all genes on the X and Y chromosomes from the count matrix.”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Mouse limb buds dissected at embryonic day 11.5 have not yet received spinal cord axonal innervation.
“we dissected mouse limb buds at embryonic day 11.5 (E11.5) before spinal cord axonal innervation”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Variants of ECM combinations, micropatterned 2D mono-culture or co-culture237,238, cell sheets239, stacked 3D structures26, and micro-positioned ECM substrates70,240 allow the formation of reproducible tissue structures and functions with a high degree of spatiotemporal control such as stretching241 and osmotic forces242 (FIG. 5).”
From Organoids (2022) · cites this paper as [237]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
“Gene expression profiles of 4,175 and 3,173 cells were recovered for hSpS with or without DAPT, respectively”
§ Generation of Functional Human 3D Cortico-Motor Assembloids > STAR★METHODS > METHOD DETAILS
Reported 7888 · recomputed 7348
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Metadata
- Authors
- Andersen, J., Revah, O., Miura, Y., Thom, N., Amin, N. D., Kelley, K. W., Singh, M., Chen, X., Thete, M. V., Walczak, E. M., Vogel, H., Fan, H. C., & Paşca, S. P.
- Affiliations
- Stanford Medicine (US)
- BD Biosciences (United States) (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 183
- Issue
- 7
- Pages
- 1913-1929.e26
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8711252
- OpenAlex
- W3111725926
- Semantic Scholar
- efd4826167926999032fda07b3500f99ab4d42ee
- Cited by
- 593
- References
- 75
- Citations by year
- 2026: 96 · 2025: 127 · 2024: 123 · 2023: 80 · 2022: 88 · 2021: 79
- FWCI
- 20.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- New York Stem Cell Foundation
- Chan Zuckerberg Initiative
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
- Keywords
- spinal cord organoids, hindbrain, corticofugal neurons, motor neurons, muscle contraction, glutamate uncaging, optogenetic stimulation, calcium imaging, patch-clamp recording
- MeSH terms
- Animals, Calcium, Cell Differentiation, Cells, Cultured, Cerebral Cortex, Cervical Vertebrae, Gene Expression Regulation, Glutamates, Humans, Motor Cortex, Muscles, Nerve Net, Organoids, Rhombencephalon, Spinal Cord, Spheroids, Cellular, Myoblasts, Mice, Induced Pluripotent Stem Cells, Optogenetics
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