Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Stavely, Rhian; Bhave, Sukhada; Ho, Wing Lam N.; Ahmed, Minhal; Pan, Weikang; Rahman, Ahmed A.; Ulloa, Jessica; Bousquet, Nicole; Omer, Meredith; Guyer, Richard A.; Nagy, Nándor; Goldstein, Allan M.; Hotta, Ryo

doi:10.1002/stem.3388

Cited by 26 publications

(21 citation statements)

References 61 publications

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“…Live cell imaging was performed as previously described. 28 Changes of GFP intensity, indicative of calcium activity, in up to 35-selected cells in 3 separate preparations were evaluated in response to varying doses of acetylcholine (ACh, Fig. 4E ʹ), demonstrating activation in a significant proportion of cells as compared to control ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Schwann Cells in the Aganglionic Colon of Hirschsprung Disease Can Generate Neurons for Regenerative Therapy

Pan

Rahman

Stavely

et al. 2022

Stem Cells Translational Medicine

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Cell therapy offers the potential to replace the missing enteric nervous system (ENS) in patients with Hirschsprung disease (HSCR) and to restore gut function. The Schwann cell (SC) lineage has been shown to generate enteric neurons pre- and post-natally. Here, we aimed to isolate SCs from the aganglionic segment of HSCR and to determine their potential to restore motility in the aganglionic colon. Proteolipid protein 1 (PLP1) expressing SCs were isolated from the extrinsic nerve fibers present in the aganglionic segment of postnatal mice and patients with HSCR. Following 7-10 days of in vitro expansion, HSCR-derived SCs were transplanted into the aganglionic mouse colon ex vivo and in vivo. Successful engraftment and neuronal differentiation were confirmed immunohistochemically and calcium activity of transplanted cells was demonstrated by live cell imaging. Organ bath studies revealed the restoration of motor function in the recipient aganglionic smooth muscle. These results show that SCs isolated from the aganglionic segment of HSCR mouse can generate functional neurons within the aganglionic gut environment and restore the neuromuscular activity of recipient mouse colon. We conclude that HSCR-derived SCs represent a potential autologous source of neural progenitor cells for regenerative therapy in HSCR.

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Section: Resultsmentioning

confidence: 99%

Schwann Cells in the Aganglionic Colon of Hirschsprung Disease Can Generate Neurons for Regenerative Therapy

Pan

Rahman

Stavely

et al. 2022

Stem Cells Translational Medicine

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“…Enteric neurons in the hindgut are derived from separate vagal and sacral neural crest cells [ 23 , 24 ]. Neural spheres extracted from colons of E13.5d mice mainly contain neural crest cells (NCCs) ( Figure S2A–E ) and enteric mesenchymal cells (EMCs) [ 25 , 26 ], while reciprocal induction of EMCs and NCCs promotes the development of the gut [ 27 ]. One study also showed that neural spheres could improve their function after being transplanted into an aganglionic embryonic distal colon [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Double C2 Domain Alpha Promotes the Formation of Hyperplastic Nerve Fibers in Aganglionic Segments of Hirschsprung’s Disease

Xiao

Meng

Chen

et al. 2022

IJMS

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Hirschsprung’s disease (HSCR) is a common developmental anomaly of the gastrointestinal tract in children. The most significant characteristics of aganglionic segments in HSCR are hyperplastic extrinsic nerve fibers and the absence of endogenous ganglion plexus. Double C2 domain alpha (DOC2A) is mainly located in the nucleus and is involved in Ca2+-dependent neurotransmitter release. The loss function of DOC2A influences postsynaptic protein synthesis, dendrite morphology, postsynaptic receptor density and synaptic plasticity. It is still unknown why hyperplastic extrinsic nerve fibers grow into aganglionic segments in HSCR. We detected the expression of DOC2A in HSCR aganglionic segment colons and established three DOC2A-knockdown models in the Neuro-2a cell line, neural spheres and zebrafish separately. First, we detected the protein and mRNA expression of DOC2A and found that DOC2A was negatively correlated with AChE+ grades. Second, in the Neuro-2a cell lines, we found that the amount of neurite outgrowth and mean area per cell were significantly increased, which suggested that the inhibition of DOC2A promotes nerve fiber formation and the neuron’s polarity. In the neural spheres, we found that the DOC2A knockdown was manifested by a more obvious connection of nerve fibers in neural spheres. Then, we knocked down Doc2a in zebrafish and found that the down-regulation of Doc2a accelerates the formation of hyperplastic nerve fibers in aganglionic segments in zebrafish. Finally, we detected the expression of MUNC13-2 (UNC13B), which was obviously up-regulated in Grade3/4 (lower DOC2A expression) compared with Grade1/2 (higher DOC2A expression) in the circular muscle layer and longitudinal muscle layer. The expression of UNC13B was up-regulated with the knocking down of DOC2A, and there were protein interactions between DOC2A and UNC13B. The down-regulation of DOC2A may be an important factor leading to hyperplastic nerve fibers in aganglionic segments of HSCR. UNC13B seems to be a downstream molecule to DOC2A, which may participate in the spasm of aganglionic segments of HSCR patient colons.

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“…Wholemount staining of LMMP tissues was performed as previously reported [ 62 , 63 ]. Tissues were incubated with blocking buffer containing 10% donkey serum, 10% bovine serum albumin, and 1% Triton X-100 for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy

Ott

Han

Mueller

et al. 2023

IJMS

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Neurons and glia of the peripheral nervous system are derived from progenitor cell populations, originating from embryonic neural crest. The neural crest and vasculature are intimately associated during embryonic development and in the mature central nervous system, in which they form a neurovascular unit comprised of neurons, glia, pericytes, and vascular endothelial cells that play important roles in health and disease. Our group and others have previously reported that postnatal populations of stem cells originating from glia or Schwann cells possess neural stem cell qualities, including rapid proliferation and differentiation into mature glia and neurons. Bone marrow receives sensory and sympathetic innervation from the peripheral nervous system and is known to contain myelinating and unmyelinating Schwann cells. Herein, we describe a population of neural crest-derived Schwann cells residing in a neurovascular niche of bone marrow in association with nerve fibers. These Schwann cells can be isolated and expanded. They demonstrate plasticity in vitro, generating neural stem cells that exhibit neurogenic potential and form neural networks within the enteric nervous system in vivo following transplantation to the intestine. These cells represent a novel source of autologous neural stem cells for the treatment of neurointestinal disorders.

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Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Cited by 26 publications

References 61 publications

Schwann Cells in the Aganglionic Colon of Hirschsprung Disease Can Generate Neurons for Regenerative Therapy

Schwann Cells in the Aganglionic Colon of Hirschsprung Disease Can Generate Neurons for Regenerative Therapy

Down-Regulation of Double C2 Domain Alpha Promotes the Formation of Hyperplastic Nerve Fibers in Aganglionic Segments of Hirschsprung’s Disease

Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy

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