Dedifferentiation of Lineage-Committed Cells by a Small Molecule

Chen, Shuibing; Zhang, Qisheng; Wu, Xu; Schultz, Peter G.; Ding, Sheng

doi:10.1021/ja037390k

Cited by 281 publications

(232 citation statements)

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“…Two small purine molecules dubbed myoseverin and reversine that cause cellularization of C2C12 mouse myofibers have been screened from combinatorial chemical libraries (Chen, Zhang, Wu, Schultz, & Ding, 2004; Rosania et al., 2000). Myoseverin disrupted microtubules and upregulated genes for growth factors, immunomodulatory molecules, ECM remodeling proteases, and stress‐response genes, consistent with the activation of pathways involved in wound healing and regeneration, but did not activate the whole program of myogenic dedifferentiation in newt limbs (Duckmanton, Kumar, Chang, & Brockes, 2005).…”

Section: Formation Of the Accumulation Blastemamentioning

confidence: 99%

Mechanisms of urodele limb regeneration

Stocum

2017

Regeneration

109

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This review explores the historical and current state of our knowledge about urodele limb regeneration. Topics discussed are (1) blastema formation by the proteolytic histolysis of limb tissues to release resident stem cells and mononucleate cells that undergo dedifferentiation, cell cycle entry and accumulation under the apical epidermal cap. (2) The origin, phenotypic memory, and positional memory of blastema cells. (3) The role played by macrophages in the early events of regeneration. (4) The role of neural and AEC factors and interaction between blastema cells in mitosis and distalization. (5) Models of pattern formation based on the results of axial reversal experiments, experiments on the regeneration of half and double half limbs, and experiments using retinoic acid to alter positional identity of blastema cells. (6) Possible mechanisms of distalization during normal and intercalary regeneration. (7) Is pattern formation is a self‐organizing property of the blastema or dictated by chemical signals from adjacent tissues? (8) What is the future for regenerating a human limb?

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Section: Formation Of the Accumulation Blastemamentioning

confidence: 99%

Mechanisms of urodele limb regeneration

Stocum

2017

Regeneration

109

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“…Dismantling of phenotypic structure and function is most visible in myofibers, but the molecular details of the process are largely uninvestigated for all limb cell types. A synthetic trisubstituted purine called myoseverin has been isolated from a combinatorial chemical library and found to cellularize C2C12 myotubes in vitro (Rosania et al, 2000;Chen et al, 2004). Myoseverin disrupts microtubules and upregulates genes for growth factors, immunomodulatory molecules, ECM remodeling proteases, and stress-response genes, consistent with the activation of pathways involved in wound healing and regeneration (Rosania et al, 2000), but does not activate the whole program of myogenic dedifferentiation (Duckmanton et al, 2005).…”

Section: Mechanisms Of Histolysis and Dedifferentiationmentioning

confidence: 99%

Looking proximally and distally: 100 years of limb regeneration and beyond

Stocum

Cameron

2011

Developmental Dynamics

106

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The experimental study of amphibian limb regeneration spans most of the 20 th century and the first decade of the 21 st century. We first review the major questions investigated over this time span: (1) the origin of regeneration blastema cells, the mechanism of tissue breakdown that liberates cells from their tissue organization to participate in blastema formation, (3) the mechanism of dedifferentiation of these cells, (4) how the blastema grows, (5) how the blastema is patterned to restore the missing limb structures, and (6) why adult anurans, birds and mammals do not have the regenerative powers of urodele salamanders. We then look forward in a perspective to discuss the many unanswered questions raised by investigations of the past century, what new approaches can be taken to answer them, and what the prospects are for translation of basic research on limb regeneration into clinical means to regenerate human appendages. Developmental Dynamics 240:943-968,

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“…Recent studies suggest that dedifferentiation may be also possible in mammalian system (Odelberg et al, 2000;Tsai et al, 2002;Chen et al, 2004). Especially, the recent reports have shown that ectopic expression of msx1 in C2C12 myotubes can induce dedifferentiation of the myotubes to produce multipotent mononucleated cells (Odelberg et al, 2000), and a 2,6-disubstituted purine, reversine, can also induce dedifferentiation of C2C12 myoblasts to become mesenchymal progenitor cells (Chen et al, 2004). However, the C2C12 myogenic line may be heterogeneous because there is this novel evidence for a resident subset of cells with side population (SP) phenotype in the C2C12 line (Benchaouir et al, 2004), whereas SP cells themselves are growth-arrested and delayed in their ability to differentiate with behaving as multipotent stem cells (Zhou et al, 2001;Jankowski et al, 2002;Tamaki et al, 2003).…”

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confidence: 99%

“…These clone were further expanded in 25-cm 2 uncoated tissue-culture flasks to grow as spheres in suspension over the course of 8 wk (Figure 3Ac). We determined that cells in these clones could divide for more than 20 passages.One biochemical indicator of myoblast dedifferentiation would be the expression loss of Myf5 and MyoD, the markers of myogenic lineage-committed myoblasts (Odelberg et al, 2000;Parker et al, 2003;Chen et al, 2004). To investigate whether MBPCs are, in fact, the dedifferentiated myoblasts induced by CNTF, we investigated the expression levels of Myf5 and MyoD in the MBPCs.…”

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confidence: 99%

Dedifferentiation of Adult Human Myoblasts Induced by Ciliary Neurotrophic Factor In Vitro

Chen

Mao

Liu³

et al. 2005

MBoC

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Ciliary neurotrophic factor (CNTF) is primarily known for its important cellular effects within the nervous system. However, recent studies indicate that its receptor can be highly expressed in denervated skeletal muscle. Here, we investigated the direct effect of CNTF on skeletal myoblasts of adult human. Surprisingly, we found that CNTF induced the myogenic lineage-committed myoblasts at a clonal level to dedifferentiate into multipotent progenitor cells-they not only could proliferate for over 20 passages with the expression absence of myogenic specific factors Myf5 and MyoD, but they were also capable of differentiating into new phenotypes, mainly neurons, glial cells, smooth muscle cells, and adipocytes. These "progenitor cells" retained their myogenic memory and were capable of redifferentiating into myotubes. Furthermore, CNTF could activate the p44/p42 MAPK and down-regulate the expression of myogenic regulatory factors (MRFs). Finally, PD98059, a specific inhibitor of p44/p42 MAPK pathway, was able to abolish the effects of CNTF on both myoblast fate and MRF expression. Our results demonstrate the myogenic lineage-committed human myoblasts can dedifferentiate at a clonal level and CNTF is a novel regulator of skeletal myoblast dedifferentiation via p44/p42 MAPK pathway. INTRODUCTIONAdult skeletal myoblasts have long been considered as myogenic lineage-committed cells with either self-renewing or differentiating into multinucleated myotubes in vitro (Jankowski et al., 2002;Tamaki et al., 2003). Myoblast fate is critically dependent on the myogenic regulatory factors (MRFs): MyoD, Myf5, myogenin, and Mrf4, which have a well-defined role in orchestrating skeletal muscle development and differentiation. Gene targeting in mice has illustrated the essential role for MRFs: Myf5 and MyoD is critical to establishing the myogenic cell lineage and producing committed, undifferentiated myoblasts (Kablar et al., 1999), whereas myogenin has an important role in initiating differentiation (Hasty et al., 1993); Mrf4 regulates terminal differentiation and myofiber maintenance (Patapoutian et al., 1995). Gene targeting in mice has illustrated the essential role for Myf5 and MyoD in myoblast fates. In MyoDϪ/Ϫ and/or Myf5Ϫ/Ϫ knockout mice, muscle precursors acquire nonmuscle cell fates (Kablar et al., 1999) and become multipotential stem cells or a progenitor compartment (Parker et al., 2003). Early histological studies indicated that muscle fibers at the amputation plane of urodele amphibians might dedifferentiate by budding off mononucleate cells from syncytial muscle cells (Echeverri and Tanaka, 2002). Recent studies suggest that dedifferentiation may be also possible in mammalian system (Odelberg et al., 2000;Tsai et al., 2002;Chen et al., 2004). Especially, the recent reports have shown that ectopic expression of msx1 in C2C12 myotubes can induce dedifferentiation of the myotubes to produce multipotent mononucleated cells (Odelberg et al., 2000), and a 2,6-disubstituted purine, reversine, can also induce dedifferentia...

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Dedifferentiation of Lineage-Committed Cells by a Small Molecule

Cited by 281 publications

References 9 publications

Mechanisms of urodele limb regeneration

Mechanisms of urodele limb regeneration

Looking proximally and distally: 100 years of limb regeneration and beyond

Dedifferentiation of Adult Human Myoblasts Induced by Ciliary Neurotrophic Factor In Vitro

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