Abstract
The human skeleton is renewed and regenerated throughout life, by a cellular process known as bone remodeling. Stem cells are clono-genic cells that are capable of differentiation into multiple mature cell types (multipotency), and simultaneously replenishing stem cell pool (self-renewal), which allows them to sustain tissue development and maintenance. Circulating mesenchymal stromal/stem cells (MSCs), are mobile adult stem cells with specific gene expression profiling, as well as enhanced mitochondrial remodeling as a promising source for personalized cell and gene therapy. A global LGR5-associated genetic interaction network highlights the functional organization and molecular phenotype of circulating MSCs.
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Change institution
Buy or subscribe
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Learn more
Buy this article
Purchase on SpringerLink
Instant access to full article PDF
Buy now
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Log in
Learn about institutional subscriptions
Read our FAQs
Contact customer support
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Data availability
All data are available upon request.
References
Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell. 2000;100:157–68. https://doi.org/10.1016/s0092-8674(00)81692-x.
ArticlePubMedGoogle Scholar
Nombela-Arrieta C, Ritz J, Silberstein LE. The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol. 2011;12:126–31. https://doi.org/10.1038/nrm3049.
ArticlePubMedPubMed CentralGoogle Scholar
Lin W, et al. Mesenchymal stem cells homing to improve bone healing. J Orthop Transl. 2017;9:19–27. https://doi.org/10.1016/j.jot.2017.03.002.
ArticleGoogle Scholar
Lin W, Xu L, Li G. A novel protocol for isolation and culture of multipotent progenitor cells from human urine. J Orthop Translation. 2019;19:12–17.
ArticleGoogle Scholar
Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M. Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science. 2005;308:1472–7.
ArticlePubMedGoogle Scholar
Caplan AI. The mesengenic process. Clin Plast Surg. 1994;21:429–35.
ArticlePubMedGoogle Scholar
Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med. 2001;7:259–64. https://doi.org/10.1016/s1471-4914(01)02016-0.
ArticlePubMedGoogle Scholar
Abdallah B, Kassem M. Human mesenchymal stem cells: from basic biology to clinical applications. Gene Ther. 2008;15:109–16.
ArticlePubMedGoogle Scholar
Bianco P, Robey PG. Marrow stromal stem cells. J Clin Investig. 2000;105:1663–8.
ArticlePubMedPubMed CentralGoogle Scholar
Forte D, et al. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy. Cell Metab. 2020;32:829–43. https://doi.org/10.1016/j.cmet.2020.09.001.
ArticlePubMedPubMed CentralGoogle Scholar
To LB, Haylock DN, Simmons PJ, Juttner CA. The biology and clinical uses of blood stem cells. Blood. 1997;89:2233–58.
ArticlePubMedGoogle Scholar
He Q, Wan C, Li G. Concise review: multipotent mesenchymal stromal cells in blood. Stem Cells. 2007;25:69–77. https://doi.org/10.1634/stemcells.2006-0335.
ArticlePubMedGoogle Scholar
Ojeda-Uribe M, et al. Bloodstream Progenitor-Cell Traffic In Primary Myelofibrosis Reveals Cell Subsets Showing Some Features Of Very-Small Embryonnic-Like Stem Cells (VSELs), Along With Endothelial (PEC), Mesenchymal (MPC) and Hematopoietic (HPC) Progenitor Cells. Blood. 2013; 122, https://doi.org/10.1182/blood.V122.21.5265.5265.
Lin W, et al. Characterisation of multipotent stem cells from human peripheral blood using an improved protocol. J Orthop Transl. 2019;19:18–28. https://doi.org/10.1016/j.jot.2019.02.003.
ArticleGoogle Scholar
Mansilla E, et al. Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: New evidence for their use in regenerative medicine. Transplant. 2006;P 38:967–9. https://doi.org/10.1016/j.transproceed.2006.02.053.
ArticleGoogle Scholar
Alm JJ, et al. Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients. J Orthop Res. 2010;28:1634–42. https://doi.org/10.1002/jor.21167.
ArticlePubMedGoogle Scholar
Roufosse CA, Direkze NC, Otto WR, Wright NA. Circulating mesenchymal stem cells. Int J Biochem Cell Biol. 2004;36:585–97. https://doi.org/10.1016/j.biocel.2003.10.007.
ArticlePubMedGoogle Scholar
Champlin RE, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood, J Am Soc Hematol. 2000;95:3702–9.
Google Scholar
Zvaifler NJ, et al. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res. 2000;2:477–88. https://doi.org/10.1186/ar130.
ArticlePubMedPubMed CentralGoogle Scholar
Xu LL, Li G. Circulating mesenchymal stem cells and their clinical implications. J Orthop Transl. 2014;2:1–7. https://doi.org/10.1016/j.jot.2013.11.002.
ArticleGoogle Scholar
Feehan J, Kassem M, Pignolo RJ, Duque G. Bone From Blood: Characteristics and Clinical Implications of Circulating Osteogenic Progenitor (COP) Cells. J Bone Min Res. 2021;36:12–23. https://doi.org/10.1002/jbmr.4204.
ArticleGoogle Scholar
Feehan J, et al. Higher Levels of Circulating Osteoprogenitor Cells Are Associated With Higher Bone Mineral Density and Lean Mass in Older Adults: A Cross-Sectional Study. JBMR. 2021;5:e10561 https://doi.org/10.1002/jbm4.10561.
ArticleGoogle Scholar
Chen YR, et al. The Use of Peripheral Blood-Derived Stem Cells for Cartilage Repair and Regeneration In Vivo: A Review. Front Pharm. 2020;11:404 https://doi.org/10.3389/fphar.2020.00404.
ArticleGoogle Scholar
Lin W, et al. Alleviation of osteoarthritis by intra-articular transplantation of circulating mesenchymal stem cells. Biochem Biophys Res Commun. 2022;636:25–32.
ArticlePubMedGoogle Scholar
Wölfel EM, et al. Senescence of skeletal stem cells and their contribution to age-related bone loss. Mechanisms Ageing Dev. 2024;221:111976.
ArticleGoogle Scholar
Ye Z, et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood. J Am Soc Hematol. 2009;114:5473–80.
Google Scholar
Yin JQ, Zhu J, Ankrum JA. Manufacturing of primed mesenchymal stromal cells for therapy. Nat Biomed Eng. 2019;3:90–104.
ArticlePubMedGoogle Scholar
Rochefort GY, et al. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006;24:2202–8.
ArticlePubMedGoogle Scholar
Liu G-Y, et al. Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential. Cell Mol Immunol. 2016;13:369–78.
ArticlePubMedGoogle Scholar
Hoang DM, et al. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022;7:1–41.
Google Scholar
Starckx S, Van den Steen PE, Wuyts A, Van Damme J, Opdenakker G. Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization. Leuk Lymphoma. 2002;43:233–41. https://doi.org/10.1080/10428190290005982.
ArticlePubMedGoogle Scholar
Pelus LM, Broxmeyer HE. Peripheral blood stem cell mobilization; a look ahead. Curr Stem Cell Rep. 2018;4:273–81. https://doi.org/10.1007/s40778-018-0141-9.
ArticlePubMedPubMed CentralGoogle Scholar
Hotten G, Neidhardt H, Jacobowsky B, Pohl J. Cloning and expression of recombinant human growth/differentiation factor 5. Biochem Biophys Res Commun. 1994;204:646–52. https://doi.org/10.1006/bbrc.1994.2508.
ArticlePubMedGoogle Scholar
Buxton P, Edwards C, Archer CW, Francis-West P. Growth/differentiation factor-5 (GDF-5) and skeletal development. J Bone Jt Surg Am. 2001;1:S23–30.
Google Scholar
Bae MS, et al. Photo-cured hyaluronic acid-based hydrogels containing growth and differentiation factor 5 (GDF-5) for bone tissue regeneration. Bone. 2014;59:189–98. https://doi.org/10.1016/j.bone.2013.11.019.
ArticlePubMedGoogle Scholar
Nakamura K, et al. p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp Cell Res. 1999;250:351–63. https://doi.org/10.1006/excr.1999.4535.
ArticlePubMedGoogle Scholar
Feng G, Wan Y, Balian G, Laurencin CT, Li X. Adenovirus-mediated expression of growth and differentiation factor-5 promotes chondrogenesis of adipose stem cells. Growth Factors. 2008;26:132–42. https://doi.org/10.1080/08977190802105917.
ArticlePubMedPubMed CentralGoogle Scholar
Li X, et al. GDF-5 induces epidermal stem cell migration via RhoA-MMP9 signalling. J Cell Mol Med. 2021;25:1939–48. https://doi.org/10.1111/jcmm.15925.
ArticlePubMedGoogle Scholar
Chen AS, et al. Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway. Plos One. 2011;6:e27586 https://doi.org/10.1371/journal.pone.0027586.
ArticlePubMedPubMed CentralGoogle Scholar
Ludwig MG, et al. Proton-sensing G-protein-coupled receptors. Nature. 2003;425:93–98. https://doi.org/10.1038/nature01905.
ArticlePubMedGoogle Scholar
Christensen BN, Kochukov M, McNearney TA, Taglialatela G, Westlund KN. Proton-sensing G protein-coupled receptor mobilizes calcium in human synovial cells. Am J Physiol Cell Physiol. 2005;289:C601–608. https://doi.org/10.1152/ajpcell.00039.2005.
ArticlePubMedGoogle Scholar
Luchsinger LL, de Almeida MJ, Corrigan DJ, Mumau M, Snoeck H-W. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529:528–31.
ArticlePubMedPubMed CentralGoogle Scholar
Huang X, et al. Sequences flanking the transmembrane segments facilitate mitochondrial localization and membrane fusion by mitofusin. Proc Natl Acad Sci USA. 2017;114:E9863–E9872. https://doi.org/10.1073/pnas.1708782114.
ArticlePubMedPubMed CentralGoogle Scholar
Iwafuchi-Doi M, Zaret KS. Cell fate control by pioneer transcription factors. Development. 2016;143:1833–7. https://doi.org/10.1242/dev.133900.
ArticlePubMedPubMed CentralGoogle Scholar
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. https://doi.org/10.1016/j.cell.2006.07.024.
ArticlePubMedGoogle Scholar
Tsang SM, Oliemuller E, Howard BA. Regulatory roles for SOX11 in development, stem cells and cancer. Semin Cancer Biol. 2020;67:3–11. https://doi.org/10.1016/j.semcancer.2020.06.015.
ArticlePubMedGoogle Scholar
Xu L, et al. Sox11-modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs. FASEB J. 2015;29:1143–52. https://doi.org/10.1096/fj.14-254169.
ArticlePubMedGoogle Scholar
Yu F, et al. Wnt7b-induced Sox11 functions enhance self-renewal and osteogenic commitment of bone marrow mesenchymal stem cells. Stem Cells. 2020;38:1020–33. https://doi.org/10.1002/stem.3192.
ArticlePubMedGoogle Scholar
Kamachi Y, Kondoh H. Sox proteins: regulators of cell fate specification and differentiation. Development. 2013;140:4129–44. https://doi.org/10.1242/dev.091793.
ArticlePubMedGoogle Scholar
Dodonova SO, Zhu F, Dienemann C, Taipale J, Cramer P. Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function. Nature. 2020;580:669–72. https://doi.org/10.1038/s41586-020-2195-y.
ArticlePubMedGoogle Scholar
Akiyama H, et al. Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. Proc Natl Acad Sci. 2005;102:14665–70.
Stöckl S, et al. Sox9 modulates cell survival and adipogenic differentiation of multipotent adult rat mesenchymal stem cells. J Cell Sci. 2013;126:2890–2.
Birchmeier W. Orphan receptors find a home. Nature. 2011;476:287–8.
ArticlePubMedGoogle Scholar
Leung C, Tan SH, Barker N. Recent advances in Lgr5+ stem cell research. Trends Cell Biol. 2018;28:380–91.
ArticlePubMedGoogle Scholar
Leung C, et al. Lgr5 Marks Adult Progenitor Cells Contributing to Skeletal Muscle Regeneration and Sarcoma Formation. Cell Rep. 2020;33:108535 https://doi.org/10.1016/j.celrep.2020.108535.
ArticlePubMedGoogle Scholar
Lin W, et al. Lgr5-overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics. FASEB J. 2019;33:8565–77. https://doi.org/10.1096/fj.201900082RR.
ArticlePubMedGoogle Scholar
Yang LV, et al. Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol. 2007;27:1334–47.
ArticlePubMedGoogle Scholar
Xue C, Bahn Y-S, Cox GM, Heitman J. G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans. Mol Biol cell. 2006;17:667–79.
ArticlePubMedPubMed CentralGoogle Scholar
Aulestia FJ, et al. Quiescence status of glioblastoma stem-like cells involves remodelling of Ca2+ signalling and mitochondrial shape. Sci Rep. 2018;8:1–12.
ArticleGoogle Scholar
Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol. 2001;69:522–30.
ArticlePubMedGoogle Scholar
Loeffler J, Duda GN, Sass FA, Dienelt A. The metabolic microenvironment steers bone tissue regeneration. Trends Endocrinol Metab. 2018;29:99–110.
ArticlePubMedGoogle Scholar
Charruyer A, Ghadially R. Influence of pH on skin stem cells and their differentiation. pH Skin: Issues Chall. 2018;54:71–78.
Google Scholar
Wang S, et al. Alkaline activation of endogenous latent TGFβ1 by an injectable hydrogel directs cell homing for in situ complex tissue regeneration. Bioact Mater. 2022;15:316–29.
PubMedGoogle Scholar
Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE. Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide. Mol Biol cell. 2002;13:2909–18.
ArticlePubMedPubMed CentralGoogle Scholar
Pedro MP, Lund K, Iglesias-Bartolome R. The landscape of GPCR signaling in the regulation of epidermal stem cell fate and skin homeostasis. Stem Cells. 2020;38:1520–31.
ArticleGoogle Scholar
Wang X, et al. pH-responsive, self-sculptured Mg/PLGA composite microfibers for accelerated revascularization and soft tissue regeneration. Biomater Adv. 2024;158:213767.
ArticlePubMedGoogle Scholar
Baran K, et al. The Expression Level of SOX Family Transcription Factors’ mRNA as a Diagnostic Marker for Osteoarthritis. J Clin Med. 2025;14:1176.
ArticlePubMedPubMed CentralGoogle Scholar
Nath SC, Harper L, Rancourt DE. Cell-Based Therapy Manufacturing in Stirred Suspension Bioreactor: Thoughts for cGMP Compliance. Front Bioeng Biotechnol. 2020;8:599674 https://doi.org/10.3389/fbioe.2020.599674.
ArticlePubMedPubMed CentralGoogle Scholar
Giner, M, et al. Circulating Osteogenic Progenitor Cells Enhanced with Teriparatide or Denosumab Treatment. J Clin Med. 11, https://doi.org/10.3390/jcm11164749 (2022).
Download references
Acknowledgements
This study was supported by grants from National Natural Science Foundation of China (82172430, 81871778, 81873326); InnoHK, Hong Kong Special Administrative Region, P. R. China; University Grants Committee, Research Grants Council of Hong Kong SAR, P.R. China (14108720, C7030-18G); NHS Foundation Trust; British Heart Foundation; Barts Charity; Lui Che Woo Foundation Limited. Fig. 4 was analysed and created via online STRING database (https://string-db.org/).
Funding
Open Access funding enabled and funded by InnoHK programme.
Author information
Authors and Affiliations
Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China
Weiping Lin & Micky Daniel Tortorella
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Weiping Lin
Key Laboratory of Orthopaedics & Traumatology, Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong, Guangzhou, China
Liangliang Xu
Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, SAR, China
Gang Li
Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Gang Li
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
Micky Daniel Tortorella
Authors
Weiping Lin
View author publications
You can also search for this author in PubMedGoogle Scholar
2. Liangliang Xu
View author publications
You can also search for this author in PubMedGoogle Scholar
3. Gang Li
View author publications
You can also search for this author in PubMedGoogle Scholar
4. Micky Daniel Tortorella
View author publications
You can also search for this author in PubMedGoogle Scholar
Contributions
G.L., M.T.: conceptualization, study design, validation, writing-draft editing. W.L., L.X.: sample collection, bioinformatic analysis, data interpretation, writing-original draft. All authors read and approved the final version of manuscript.
Corresponding authors
Correspondence to Liangliang Xu, Gang Li or Micky Daniel Tortorella.
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval and informed consent
All patients provided written informed consent for research studies. All human studies were approved by Clinical Research and Ethics Committee of The Chinese University of Hong Kong and Guangzhou University of Chinese Medicine.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Reprints and permissions
About this article
Check for updates. Verify currency and authenticity via CrossMark
Cite this article
Lin, W., Xu, L., Li, G. et al. Molecular gene signature of circulating stromal/stem cells. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01322-4
Download citation
Received:27 November 2024
Revised:02 February 2025
Accepted:06 February 2025
Published:12 March 2025
DOI:https://doi.org/10.1038/s10038-025-01322-4
Share this article
Anyone you share the following link with will be able to read this content:
Get shareable link
Sorry, a shareable link is not currently available for this article.
Copy to clipboard
Provided by the Springer Nature SharedIt content-sharing initiative