Frustrated differentiation of mesenchymal stem cells
Mesenchymal stem cells (MSCs) are one of the most useful cell resources for clinical application in regenerative medicine. However, standardization and quality assurance of MSCs are still essential problems because the stemness of MSCs depends on such factors as the collection method, individual differences associated with the source, and cell culture history. As such, the establishment of culture techniques which assure the stemness of MSCs is of vital importance. One important factor affecting MSCs during culture is the effect of the mechanobiological memory of cultured MSCs built up by their encounter with particular mechanical properties of the extracellular mechanical milieu. How can we guarantee that MSCs will remain in an undifferentiated state? Procedures capable of eliminating effects related to the history of the mechanical dose for cultured MSCs are required. For this problem, we have tried to establish the design of microelastically patterned cell-culture matrix which can effectively induce mechanical oscillations during the period of nomadic migration of cells among different regions of the matrix. We have previously observed before that the MSCs exposed to such a growth regimen during nomadic culture keep their undifferentiated state—with this maintenance of stemness believed due to lack of a particular regular mechanical dosage that is likely to determine a specific lineage. We have termed this situation as “frustrated differentiation”. In this minireview, I introduce the concept of frustrated differentiation of MSCs and show possibility of purposeful regulation of this phenomenon.
KeywordsFrustrated differentiation Mesenchymal stem cells Micro elasticity patterning Matrix stiffness Stemness of MSCs
This research was supported by AMED-CREST under Grant Number JP19gm0810002.
Compliance with ethical standards
Conflict of interest
Satoru Kidoaki declares that he has no conflict of interest.
This article does not contain any studies with human participants or animals performed by the author.
- Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG (2006) Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198:54–64. https://doi.org/10.1016/j.expneurol.2005.10.029 CrossRefGoogle Scholar
- Kawano T, Kidoaki S (2011) Elasticity boundary conditions required for cell mechanotaxis on microelastically-patterned gels. Biomaterials 32:2725–2733. https://doi.org/10.1016/j.biomaterials.2011.01.009 CrossRefGoogle Scholar
- Kidoaki S, Ebata H, Sawada R, Moriyama K, Kuboki T, Tsuji Y, Kono K, Tanaka K, Sasaki S (2017) Characterization of the frustrated differentiation of mesenchymal stem cells induced by normadic migration between stiff and soft region of gel matrix. Biophys J 112(suppl.1):436a. https://doi.org/10.1016/j.bpj.2016.11.2328 CrossRefGoogle Scholar
- Liu S, Stroncek DF, Zhao Y, Chen V, Shi R, Chen J, Ren J, Liu H, Bae HJ, Highfill SL, Jin P (2019) Single cell sequencing reveals gene expression signatures associated with bone marrow stromal cell subpopulations and time in culture. J Transl Med 17:23. https://doi.org/10.1186/s12967-018-1766-2 CrossRefGoogle Scholar
- Moriyama K, Kidoaki S (2018) Cellular durotaxis revisited: initial-position-dependent determination of the threshold stiffness gradient to induce durotaxis. Langmuir. https://doi.org/10.1021/acs.langmuir.8b02529
- Okamoto T, Aoyama T, Nakayama T, Nakamata T, Hosaka T, Nishijo K, Nakamura T, Kiyono T, Yoguchida J (2002) Clonal heterogeneity in differentiation potential of immortalized human mesenchymal stem cells. BBRC 295:354–361Google Scholar
- Ueki A, Kidoaki S (2015) Manipulation of cell mechanotaxis by designing curvature of the elasticity boundary on hydrogel matrix. Biomaterials 41:45–52. https://doi.org/10.1016/j.biomaterials.2014.11.030 CrossRefGoogle Scholar
- Yoshihara T, Ohta M, Itokazu Y, Matsumoto N, Dezawa M, Suzuki Y, Taguchi A, Watanabe Y, Adachi Y, Ikehara S, Sugimoto H, Ide C (2007) Neuroprotective effect of bone marrow-derived mononuclear cells promoting functional recovery from spinal cord injury. J Neurotrauma 24:1026–1036. https://doi.org/10.1089/neu.2007.132R CrossRefGoogle Scholar