editorial exogenous and endogenous stem cells for skeletal...
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EditorialExogenous and Endogenous Stem Cells for Skeletal Regeneration
Heng Zhu ,1 Bo Yu ,2 and Liu Yang 3
1Institute of Beijing Basic Medical Sciences, Road Taiping 27, Beijing, China2Section of Restorative Dentistry, Division of Constitutive & Regenerative Sciences, UCLA School of Dentistry, Los Angeles, USA3Institute of PLA Orthopaedics & Traumatology, Xi-jing Hospital, Fourth Military Medical University, Xi’an, China
Correspondence should be addressed to Heng Zhu; [email protected], Bo Yu; [email protected],and Liu Yang; [email protected]
Received 16 October 2018; Accepted 17 October 2018; Published 18 November 2018
Copyright © 2018 Heng Zhu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The optimized applications of stem cells for skeletal recon-struction have been gaining more and more attention in thepast decades. Generally, the exogenous multipotent cells areobtained from numerous connective tissues including adi-pose tissues, bones, and cartilages; expanded in an appropri-ate cell culture system in vitro; and intravenously deliveredinto the bodies or injected into skeletal tissues. These exoge-nous stem cells are expected to arrive in the tissue niches,differentiate into specialized skeletal cells, and protect theskeletal tissues from harmful stimuli. However, the underly-ing mechanisms of the regenerative effects of exogenous stemcells and the potential influences of the in vitro expansion onthe stem cell biological characteristics remained largelyelusive, which have confined the clinical applications of stemcells for skeletal regeneration. In accordance with the thera-peutic effects of exogenous stem cells in skeletal reconstruc-tion, endogenous stem cells are known now to be involvedin skeletal repair. Upon the in vitro and in vivo stimuli, thesetissue-specific stem cells proliferate, migrate to the special-ized tissue niches, and differentiate to reconstruct the skeletalstructure and function. Also, the precise regenerative mecha-nisms of endogenous stem cells are incompletely understood.Therefore, more details of the regenerative effects of bothexogenous stem cells and endogenous stem cells, and theirunderlying mechanisms would be helpful to guide us inimproving stem cell-based skeletal reconstruction.
In this special issue, we first present a thorough review byW. Du et al. on the role of fibroblast growth factors in toothdevelopment and incisor renewal. They suggest that theformation of dental tissues, as well as the development
and homeostasis of the stem cells in the continuouslygrowing mouse incisor, is mediated by multiple FGF familymembers. They discuss the role of FGF signaling in thesemineralized tissues, trying to separate its different functionsand highlighting the crosstalk between FGFs and othersignaling pathways. In addition, the pivotal roles of the FGFfamily member in skeletal regeneration are further validatedby an original article authored by L. Huang et al. They foundthat FGF-18 had a positive impact on chondrogenic differen-tiation and matrix deposition of human adipose-derivedmesenchymal stem cells (ADSC). More importantly, syner-gistic effects of FGF-18 and TGF-β3 were observed on thechondrogenesis of the ADSCs in vitro pellet model.
Besides FGFs, platelet-derived growth factor (PDGF), apromoting factor for tissue repair, has been widely used inbone reconstruction in recent years. However, the mecha-nism by which PDGF regulates stem cell-based bone regener-ation still remained largely unelucidated. M. Zhang et al.demonstrated that PDGF-BB increased osteogenic differenti-ation but inhibited adipogenic differentiation of mesenchy-mal stem cells (MSCs). In addition, secreted PDGF-BBsignificantly enhanced human umbilical vein endothelialcell migration and angiogenesis. Most importantly, theyshowed that PDGF-BB overexpression significantly improvedMSC-mediated angiogenesis and osteogenesis in vivo by usinga critical-sized rat calvarial defect model.
Stemness is one of the distinct features of stem cells fromdifferentiated cells, which control the size of seed cell pool andthe multipotency of seed cells for skeletal regeneration. In anoriginal study from S. Zhang et al. in the current special issue,
HindawiStem Cells InternationalVolume 2018, Article ID 2574243, 2 pageshttps://doi.org/10.1155/2018/2574243
the researchers found that dorsal root ganglion (DRG) cellsenhanced the proliferation and multipotent differentiationof MSCs. In addition, DRG cells upregulated the clone-forming ability as well as the mRNA level of Sox2, Nanog,and Oct4 of MSCs. Mechanistically, they determined thatDRG cells maintain stemness of MSCs by enhancing autoph-agy through the AMPK/mTOR pathway.
Increasing evidence has demonstrated that skeletalregeneration is controlled by multiple factors and mecha-nisms. In the past decade, studies have emphasized the roleof epigenetic modulation on stem cell fate. However, thestudy results of the ubiquitin-dependent proteolysis systemin regulating bone remodeling remained controversial.Therefore, Y. Guo et al. present a thorough review on theroles of deubiquitinases in regulating differentiation and/orfunction of osteoblast and osteoclasts so as to reveal themultiple functions and mechanisms of deubiquitinases inbone remodeling.
In recent years, anti-inflammatory effects are consideredone kind of promoting mechanisms in stem cell-based skel-etal regeneration. The transplanted exogenous stem cellshave been suggested for suppressing immune complicationsand promoting tissue repair. M. Wang et al. reviewed theadvancing research on the properties of MSC-based immu-nomodulation and the rapidly developed clinical applicationof MSCs. This valuable review of MSCs provides new insightinto stem cell-mediated potential treatments for tissue dam-age and inflammation.
While numerous stem cell-based strategies have beenapplied to repair skeletal defects, these techniques exhibitcertain limitations including stem cell shortage and/ormalfunction in vivo. To overcome the challenges, cell-freestrategies attempt to reconstruct the damaged tissue byrecruiting endogenous stem cells. W. Guo et al. comparedthe advantages of cell-based techniques to the cell-free coun-terparts and summarized potential source endogenous stemcells for skeletal regeneration. In addition, numerous impor-tant recruitment factors for meniscal regeneration werediscussed. This review suggests that recruiting endogenousstem cells by cell-free techniques may play a critical role inthe future of skeletal regeneration.
Furthermore, except for the modulatory mechanisms onthe exogenous and endogenous stem cells, the microenviron-mental factors that control the stem cell niches were also dis-cussed in this special issue. A review from Q. Li et al.suggested that marrow adipose tissue (MAT) is a unique fatdepot in the bone marrow and exhibits a close relationshipwith hematopoiesis and bone homeostasis. In this review,they highlight recent advancement made in MAT regardingthe origin and distribution of MAT, the local interaction withbone homeostasis and hematopoietic niche, the systemicendocrine regulation of metabolism, and MAT-based strate-gies to enhance bone formation. They mentioned that thebone marrow niche includes a subset of skeletal stem cellscapable of generating skeletal lineages and the adipocytes inthe bone marrow share precursors with osteoblasts otherthan extramedullary adipocytes. Most importantly, they sug-gested that it may be a new strategy to promote skeletalregeneration by targeting MAT. Moreover, macrophages
recently have been found to be an important player involvedin the regulation on a stem cell niche. The strong plasticity ofmacrophages enables their dual function that changes thesurrounding stem cell niche in vivo, which favors either tissueinflammation or tissue repair, which changes. X. Jia et al.investigated the potential role of macrophages during thebone regeneration process in the femurs of rats implantedwith TCP. They found that TCP significantly suppresses theactivation of the NF-kappa B pathway and causes a decreasein EZH1 expression. The reduction of EZH1 led to lowerexpressions of M1 markers and shift macrophage polariza-tion towards the M2 phenotype. Their novel findings providevaluable insights into a new strategy that controls M2 macro-phage polarization and ultimately favors a microenviron-ment suitable for skeletal repair.
In summary, we suggest that these outstanding originalresearch articles and reviews may promote better under-standing of exogenous and endogenous stem cell-mediatedskeletal regeneration and hope the readers of this specialissue will gain more insights into the advancements and chal-lenges faced by this rapidly expanding field of medicine.
Conflicts of Interest
The authors declare that there is no conflict of interestregarding the publication of this article.
Acknowledgments
We would like to thank all reviewers and authors for theircontributions. We thank the National Natural ScienceFoundation of China Grants (nos. 81871771, 81572159,and 81572192) and the Beijing Natural Science Foundation(no. 7182123).
Heng ZhuBo Yu
Liu Yang
2 Stem Cells International
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