Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

Liu, Yang; Jiang, Xiaohua; Zhang, Xiao Hu; Chen, Rui; Sun, Tingting; Fok, Kin Lam; Dong, Jia; Tsang, Lai Ling; Yi, Shaoqiong; Ruan, Ye Chun; Guo, Jinghui; Yu, Man; Tian, Yuemin; Chung, Yiu Wa; Yang, Ming; Xu, Wei; Chung, Chin Man; Li, Tingyu; Chan, Hsiao Chang

doi:10.1002/stem.764

Cited by 39 publications

(48 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A), which is the standard method that is currently employed to induce dedifferentiation. 19,20,63 In our predifferentiated hMSCs, CON treatment resulted in a decreased osteoblast or adipocyte phenotype ( Fig. 1B-L), although cells did not completely revert to the undifferentiated state.…”

Section: Hk Suppresses Mature Phenotype Of Predifferentiated Osteoblamentioning

confidence: 83%

“…19 Similarly, in MSC-derived neural cells, withdrawal of extrinsic induction factors reverted cells back to a mesenchymal morphology and suppressed neural markers. 20 These dedifferentiation strategies, while successful, may not be practical for achieving cell dedifferentiation in a wound environment, where the contents of the microenvironment cannot be easily eliminated. Thus, there is a need for novel methods to modulate the terminal differentiated status of cells, which may enable us to implement dedifferentiation as a therapeutic strategy for improving tissue regeneration.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells

Sundelacruz

Levin²,

Kaplan³

2013

Tissue Engineering Part A

View full text Add to dashboard Cite

Although adult stem cell transplantation has been implemented as a therapy for tissue repair, it is limited by the availability of functional adult stem cells. A potential approach to generate stem and progenitor cells may be to modulate the differentiated status of somatic cells. Therefore, there is a need for a better understanding of how the differentiated phenotype of mature cells is regulated. We hypothesize that bioelectric signaling plays an important role in the maintenance of the differentiated state, as it is a functional regulator of the differentiation process in various cells and tissues. In this study, we asked whether the mature phenotype of osteoblasts and adipocytes derived from human mesenchymal stem cells (hMSCs) could be altered by modulation of their membrane potential. hMSC-derived osteoblasts and adipocytes were depolarized by treatment with ouabain, a Na(+)/K(+) ATPase inhibitor, or by treatment with high concentrations of extracellular K(+). To characterize the effect of voltage modulation on the differentiated state, the depolarized cells were evaluated for (1) the loss of differentiation markers; (2) the up-regulation of stemness markers and stem properties; and (3) differences in gene expression profiles in response to voltage modulation. hMSC-derived osteoblasts and adipocytes exhibited significant down-regulation of bone and fat tissue markers in response to depolarization, despite the presence of differentiation-inducing soluble factors, suggesting that bioelectric signaling overrides biochemical signaling in the maintenance of cell state. Suppression of the osteoblast or adipocyte phenotype was not accompanied by up-regulation of genes associated with the stem state. Thus, depolarization does not activate the stem cell genetic signature and, therefore, does not induce a full reprogramming event. However, after transdifferentiating the depolarized cells to evaluate for multi-lineage potential, depolarized osteoblasts demonstrated improved ability to achieve correct adipocyte morphology compared with nondepolarized osteoblasts. The present study thus demonstrates that depolarization reduces the differentiated phenotype of hMSC-derived cells and improves their transdifferentiation capacity, but does not restore a stem-like genetic profile. Through global transcript profiling of depolarized osteoblasts, we identified pathways that may mediate the effects of voltage signaling on cell state, which will require a detailed mechanistic inquiry in future studies.

show abstract

Section: Hk Suppresses Mature Phenotype Of Predifferentiated Osteoblamentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells

Sundelacruz

Levin²,

Kaplan³

2013

Tissue Engineering Part A

View full text Add to dashboard Cite

show abstract

“…Furthermore, the report previously demonstrated that dedifferentiated MSCs exhibited enhanced higher efficacy in neuronal redifferentiation compared to non‐manipulated MSCs 46. Dedifferentiated muscle stem cells could form neurosphere‐like structures that contained neural stem/progenitor cells 47.…”

Section: Resultsmentioning

confidence: 96%

PAC1R agonist maxadilan enhances hADSC viability and neural differentiation potential

Guo

et al. 2016

J Cellular Molecular Medi

View full text Add to dashboard Cite

Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a structurally endogenous peptide with many biological roles. However, little is known about its presence or effects in human adipose‐derived stem cells (hADSCs). In this study, the expression of PACAP type I receptor (PAC1R) was first confirmed in hADSCs. Maxadilan, a specific agonist of PAC1R, could increase hADSC proliferation as determined by Cell Counting Kit‐8 and cell cycle analysis and promote migration as shown in wound‐healing assays. Maxadilan also showed anti‐apoptotic activity in hADSCs against serum withdrawal‐induced apoptosis based on Annexin V/propidium iodide analysis and mitochondrial membrane potential assays. The anti‐apoptotic effects of maxadilan correlated with the down‐regulation of Cleaved Caspase 3 and Caspase 9 as well as up‐regulation of Bcl‐2. The chemical neural differentiation potential could be enhanced by maxadilan as indicated through quantitative PCR, Western blot and cell morphology analysis. Moreover, cytokine neural redifferentiation of hADSCs treated with maxadilan acquired stronger neuron‐like functions with higher voltage‐dependent tetrodotoxin‐sensitive sodium currents, higher outward potassium currents and partial electrical impulses as determined using whole‐cell patch clamp recordings. Maxadilan up‐regulated the Wnt/β‐catenin signalling pathway associated with dimer‐dependent activity of PAC1R, promoting cell viability that was inhibited by XAV939, and it also activated the protein kinase A (PKA) signalling pathway associated with ligand‐dependent activity of PAC1R, enhancing cell viability and neural differentiation potential that was inhibited by H‐89. In summary, these results demonstrated that PAC1R is present in hADSCs, and maxadilan could enhance hADSC viability and neural differentiation potential in neural differentiation medium.

show abstract

“…As different isoforms of miR-29 (a, b, and c) and miR-30 (a, b, c, d, and e) have conservative core sequences and their predicted targeting sites to the 3’UTR of CCNA2 or Cdk6 are highly homologous, it is likely that using antimiRs for other isoforms of miR-29 or miR-30 will have similar effects on these genes. miRNA has been demonstrated to play critical roles in the dedifferentiation and proliferation of retinal pigment cell [43], chondrocytes [44], mesenchymal stem cells [45], and Schwann cells [46]. The well-established in vitro neonatal cardiomyocyte culture model, together with adult cardiomyocyte analysis used in this study, provides insight into the molecular regulatory network that composes of mRNA, microRNA and protein.…”

Section: Discussionmentioning

confidence: 99%

Targeted MicroRNA Interference Promotes Postnatal Cardiac Cell Cycle Re-Entry

et al. 2013

View full text Add to dashboard Cite

Mammalian heart cells undergo a marked reduction in proliferative activity shortly after birth, and thereafter grow predominantly by hypertrophy. Our understanding of the molecular mechanisms underlying cardiac maturation and senescence is based largely on studies at the whole-heart level. Here, we investigate the molecular basis of the acquired quiescence of purified neonatal and adult cardiomyocytes, and use microRNA interference as a novel strategy to promote cardiomyocyte cell cycle re-entry. Expression of cyclins and cyclin-dependent kinases (CDKs) and positive modulators were down-regulated, while CDK inhibitors and negative cell cycle modulators were up-regulated during postnatal maturation of cardiomyocytes. The expression pattern of microRNAs also changed dramatically, including increases in miR-29a, miR-30a and miR-141. Treatment of neonatal cardiomyocytes with miRNA inhibitors anti-miR-29a, anti-miR-30a, and antimiR-141 resulted in more cycling cells and enhanced expression of Cyclin A2 (CCNA2). Thus, targeted microRNA interference can reactivate postnatal cardiomyocyte proliferation.

show abstract

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

Cited by 39 publications

References 71 publications

Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells

Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells

PAC1R agonist maxadilan enhances hADSC viability and neural differentiation potential

Targeted MicroRNA Interference Promotes Postnatal Cardiac Cell Cycle Re-Entry

Contact Info

Product

Resources

About