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The Progress of Stem Cell Technology for Skeletal Regeneration

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The Progress of Stem Cell Technology for Skeletal Regeneration International Journal of Molecular Sciences Review The Progress of Stem Cell Technology for Skeletal Regeneration Shoichiro Tani 1,2 , Hiroyuki Okada 1,2 , Ung-il Chung 2,3, Shinsuke Ohba 4 and Hironori Hojo 2,3,* 1 Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; [email protected] (S.T.); [email protected] (H.O.) 2 Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; [email protected] 3 Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan 4 Department of Cell Biology, Institute of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-3-5841-1427 Abstract: Skeletal disorders, such as osteoarthritis and bone fractures, are among the major conditions that can compromise the quality of daily life of elderly individuals. To treat them, regenerative therapies using skeletal cells have been an attractive choice for patients with unmet clinical needs. Currently, there are two major strategies to prepare the cell sources. The first is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which can recapitulate the skeletal developmental process and differentiate into various skeletal cells. Skeletal tissues are derived from three distinct origins: the neural crest, paraxial mesoderm, and lateral plate mesoderm. Thus, various protocols have been proposed to recapitulate the sequential process of skeletal development. The second strategy is to extract stem cells from skeletal tissues. In addition to mesenchymal stem/stromal cells (MSCs), multiple cell types have been identified as alternative cell sources. These cells have distinct multipotent properties allowing them to differentiate into skeletal cells and various potential applications for skeletal regeneration. In this review, we summarize state-of-the-art research in Citation: Tani, S.; Okada, H.; Chung, stem cell differentiation based on the understanding of embryogenic skeletal development and stem U.-i.; Ohba, S.; Hojo, H. The Progress cells existing in skeletal tissues. We then discuss the potential applications of these cell types for of Stem Cell Technology for Skeletal regenerative medicine. Regeneration. Int. J. Mol. Sci. 2021, 22, 1404. https://doi.org/10.3390/ Keywords: stem cell; mesoderm; neural crest; skeletal regeneration ijms22031404 Academic Editor: Vladimir Titorenko Received: 28 December 2020 1. Introduction Accepted: 28 January 2021 Published: 30 January 2021 Skeletal disorders, such as osteoarthritis and bone fractures, cause critical deformation and dysfunctions in skeletal tissues, resulting in a compromised quality of life, especially Publisher’s Note: MDPI stays neutral in elderly individuals [1,2]. Bone tissue has limited healing potential, but it can regenerate with regard to jurisdictional claims in itself if the quantity and quality of the injury are not too severe. In the case of severe published maps and institutional affil- fractures or massive bone loss, the injuries cannot be repaired sufficiently and lead to non- iations. union or pseudoarticulation [2]. On the other hand, articular cartilage has little or almost no potential for healing. The present therapeutic options for disorders involving the articu- lar cartilage are predominantly palliative, and include analgesics and anti-inflammatory medication; no options can heal them effectively [3]. Thus, regenerative therapies using skeletal cells or their progenitors are recognized as important therapeutic alternatives [4]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Currently, there are two major strategies for such cell therapies (Figure1). The first This article is an open access article is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which distributed under the terms and can recapitulate the skeletal developmental process and differentiate into various skeletal conditions of the Creative Commons cells. Because skeletal tissues are derived from multiple origins, multiple protocols have Attribution (CC BY) license (https:// been established based on the understanding of the skeletal development [5–7]. The creativecommons.org/licenses/by/ second strategy is to use stem cells purified from adult skeletal tissues. The extracted 4.0/). cells are usually expanded and either locally implanted or intravascularly infused [8,9]. Int. J. Mol. Sci. 2021, 22, 1404. https://doi.org/10.3390/ijms22031404 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 cells. Because skeletal tissues are derived from multiple origins, multiple protocols have Int. J. Mol. Sci. 2021, 22, 1404 been established based on the understanding of the skeletal development [5–7]. The2 ofsec- 15 ond strategy is to use stem cells purified from adult skeletal tissues. The extracted cells are usually expanded and either locally implanted or intravascularly infused [8,9]. Mes- enchymalMesenchymal stem/stromal stem/stromal cells cells (MSCs) (MSCs) are are a conventional a conventional cell cell type type that that has has been been studied and applied applied to to clinical clinical settings settings [10]. [10 In]. addition, In addition, multiple multiple cell celltypes types including including skeletal skeletal stem cellsstem (SSCs) cells (SSCs) and CXCL12-abundant and CXCL12-abundant reticular reticular (CAR (CAR)) cells have cells havebeen beenidentified identified as cell as pop- cell populationsulations with with unique unique properties properties and potentials. and potentials. These These cells have cells distinct have distinct multipotent multipotent prop- propertieserties which which allow allow them themto differentiate to differentiate into se intoveral several skeletal skeletal cell types cell [11,12]. types [ 11In, 12this]. re- In view,this review, we first we summarize first summarize the current the currentunderstan understandingding of skeletal of development skeletal development in embryos in andembryos the induction and the inductionprotocols protocolsfor recapitulating for recapitulating the developmental the developmental process with process stem cells. with Westem then cells. introduce We then MSCs introduce and MSCsthe other and stem/proge the other stem/progenitornitor cells in skeletal cells tissues. in skeletal Lastly, tissues. we discussLastly, we the discuss current the limitations current limitations and potential and a potentialpplications applications of these cell of types these for cell regenera- types for tiveregenerative medicine. medicine. Figure 1. Summary of cell therapy in skeletal re regeneration.generation. PSC, pluripotent stem cell cell;; iPSC, induced pluripotent stem cell; ESC, embryonicembryonic stem cell;cell; NC,NC, neuralneural crest;crest; PM,PM, paraxialparaxial mesoderm;mesoderm; LPM,LPM, laterallateral plateplate mesoderm;mesoderm; MSC,MSC, mesenchymalmesenchymal stem/stromalstem/stromal cell; cell; SSC, SSC, skeletal skeletal stem stem cell. cell. 2. Skeletal Development in Embryos Skeletal tissues tissues originate originate fr fromom three three distinct distinct embryonic embryonic components components according according to the to location:the location: the neural the neural crest, crest, paraxial paraxial mesoder mesoderm,m, and lateral and lateral plate plate mesoderm mesoderm [13]. [The13]. axial The skeletonaxial skeleton is derived is derived from fromthe paraxial the paraxial mesoder mesoderm,m, whereas whereas the appendicular the appendicular skeleton skeleton orig- inatesoriginates from from the lateral the lateral plate plate mesoderm. mesoderm. Most Most of the of craniofacial the craniofacial skeleton skeleton is derived is derived from thefrom neural the neural crest [13]. crest There [13]. are There two are modes two modesof bone of formation: bone formation: intramembranous intramembranous ossifica- tionossification and endochondral and endochondral ossification. ossification. In intr Inamembranous intramembranous ossification, ossification, mesenchymal mesenchymal cells directlycells directly differentiate differentiate into osteoblasts into osteoblasts that pr thatoduce produce the bone. the bone.In endochondral In endochondral ossification, ossifi- bonecation, formation bone formation occurs sequentially occurs sequentially after cartilage after cartilage formation formation [13]. The [13 neural]. The neuralcrest gener- crest atesgenerates most of most the ofcraniofacial the craniofacial skeleton skeleton via intramembranous via intramembranous ossification, ossification, with a withfew excep- a few tions,exceptions, including including the skull the base. skull base.However, However, the paraxial the paraxial and lateral and lateral plate platemesoderm mesoderm form mostform mostbones bones via endochondral via endochondral ossification ossification [13]. [Based13]. Based on the on origins the origins or mode or mode of bone of bone for- mation,formation, different different induction induction protocols protocols have have been been established established to generate to generate skeletal skeletal cells from cells humanfrom human pluripotent pluripotent stem cells stem (hPSCs) cells (hPSCs) [6,14,15] [6., 14Thus,,15]. we Thus, succinctly we succinctly overview overview the current the understandingcurrent understanding of skeletal
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