Limits...
Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.

Wyatt TJ, Rossi SL, Siegenthaler MM, Frame J, Robles R, Nistor G, Keirstead HS - Stem Cells Int (2011)

Bottom Line: In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss.In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models.The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy & Neurobiology, Reeve-Irvine Research Center, Sue and Bill Gross Stem Cell Research Center, School of Medicine, 2002 Sue and Bill Gross Hall: A CIRM Institute, University of California at Irvine, Irvine, CA 92697-4292, USA.

ABSTRACT
Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

No MeSH data available.


Related in: MedlinePlus

hMNP differentiation in vivo. Human nuclear (Ku80) antigen-positive cells were detected in all treated animals of all 3 animal models and colabeled with different motor neuron differentiation markers.  Human nuclear (Ku80) antigen-positive cells (a, c) double stained with Islet-1 ((b) red), NeuN ((d) NeuN in red, human nuclei in green), p75 ((e) p75 in red, human nuclei in green), or ChAT ((f) ChAT in blue, human nuclei in brown), consistent with a motor neuron lineage of mixed maturation state. Bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3116523&req=5

fig2: hMNP differentiation in vivo. Human nuclear (Ku80) antigen-positive cells were detected in all treated animals of all 3 animal models and colabeled with different motor neuron differentiation markers. Human nuclear (Ku80) antigen-positive cells (a, c) double stained with Islet-1 ((b) red), NeuN ((d) NeuN in red, human nuclei in green), p75 ((e) p75 in red, human nuclei in green), or ChAT ((f) ChAT in blue, human nuclei in brown), consistent with a motor neuron lineage of mixed maturation state. Bar = 50 μm.

Mentions: Human nuclear (Ku80) antigen-positive cells were detected in all transplanted animals of all 3 animal models and did not migrate from the transplant sites cranial and caudal to the injection sites (Figure (2)). Human cells (Figures 2(a) and 2(c)) double stained with the young motor neuron marker Islet-1 (Figure 2(b)) and were observed in the ventral horns of hMNP treated but not in vehicle control Δ7SMN animals. In Δ7SMN animals, human nuclear antigen-positive cells did not double label with markers for the mature motor neuron markers ChAT or SMI-32, indicating that their limited time in vivo (13 days) is insufficient for differentiation of transplanted hMNPs. However, human cells were found within the SOD1 G93A and SCI animals, in which animals were survived for up to 2 and 3 months, respectively, after transplantation. Human cells were colabeled with neuronal and motor neuron markers such as NeuN (Figure 2(d)), p75 (Figure 2(e)) and ChAT (Figure 2(f)), consistent with a motor neuron lineage of a mixed maturation state. Many human nuclear antigen-positive cells extended TUJ1-positive processes. TUJ1 tissue staining was absent in no-primary and no-secondary antibody controls. Transplanted cells did not extend axons into the periphery or form neuromuscular junctions with host tissue, as expected.


Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.

Wyatt TJ, Rossi SL, Siegenthaler MM, Frame J, Robles R, Nistor G, Keirstead HS - Stem Cells Int (2011)

hMNP differentiation in vivo. Human nuclear (Ku80) antigen-positive cells were detected in all treated animals of all 3 animal models and colabeled with different motor neuron differentiation markers.  Human nuclear (Ku80) antigen-positive cells (a, c) double stained with Islet-1 ((b) red), NeuN ((d) NeuN in red, human nuclei in green), p75 ((e) p75 in red, human nuclei in green), or ChAT ((f) ChAT in blue, human nuclei in brown), consistent with a motor neuron lineage of mixed maturation state. Bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3116523&req=5

fig2: hMNP differentiation in vivo. Human nuclear (Ku80) antigen-positive cells were detected in all treated animals of all 3 animal models and colabeled with different motor neuron differentiation markers. Human nuclear (Ku80) antigen-positive cells (a, c) double stained with Islet-1 ((b) red), NeuN ((d) NeuN in red, human nuclei in green), p75 ((e) p75 in red, human nuclei in green), or ChAT ((f) ChAT in blue, human nuclei in brown), consistent with a motor neuron lineage of mixed maturation state. Bar = 50 μm.
Mentions: Human nuclear (Ku80) antigen-positive cells were detected in all transplanted animals of all 3 animal models and did not migrate from the transplant sites cranial and caudal to the injection sites (Figure (2)). Human cells (Figures 2(a) and 2(c)) double stained with the young motor neuron marker Islet-1 (Figure 2(b)) and were observed in the ventral horns of hMNP treated but not in vehicle control Δ7SMN animals. In Δ7SMN animals, human nuclear antigen-positive cells did not double label with markers for the mature motor neuron markers ChAT or SMI-32, indicating that their limited time in vivo (13 days) is insufficient for differentiation of transplanted hMNPs. However, human cells were found within the SOD1 G93A and SCI animals, in which animals were survived for up to 2 and 3 months, respectively, after transplantation. Human cells were colabeled with neuronal and motor neuron markers such as NeuN (Figure 2(d)), p75 (Figure 2(e)) and ChAT (Figure 2(f)), consistent with a motor neuron lineage of a mixed maturation state. Many human nuclear antigen-positive cells extended TUJ1-positive processes. TUJ1 tissue staining was absent in no-primary and no-secondary antibody controls. Transplanted cells did not extend axons into the periphery or form neuromuscular junctions with host tissue, as expected.

Bottom Line: In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss.In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models.The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy & Neurobiology, Reeve-Irvine Research Center, Sue and Bill Gross Stem Cell Research Center, School of Medicine, 2002 Sue and Bill Gross Hall: A CIRM Institute, University of California at Irvine, Irvine, CA 92697-4292, USA.

ABSTRACT
Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

No MeSH data available.


Related in: MedlinePlus