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Cited by 61Mesenchymal stem cell researchBone Tissue Engineering MaterialsTissue Engineering and Regenerative Medicine

Impact of Donor Age on the Osteogenic Supportive Capacity of Mesenchymal Stromal Cell-Derived Extracellular Matrix

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Carvalho, Marta S., Alves, Laura, Bogalho, Isabel, Cabral, Joaquim M. S., da Silva, Cláudia L.·2021·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2021.747521PMC PMC8523799
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Abstract

Mesenchymal stromal cells (MSC) have been proposed as an emerging cell-based therapeutic option for regenerative medicine applications as these cells can promote tissue and organ repair. In particular, MSC have been applied for the treatment of bone fractures. However, the healing capacity of these fractures is often compromised by patient’s age. Therefore, considering the use of autologous MSC, we evaluated the impact of donor age on the osteogenic potential of bone marrow (BM)-derived MSC. MSC from older patients (60 and 80 years old) demonstrated impaired proliferative and osteogenic capacities compared to MSC isolated from younger patients (30 and 45 years old), suggesting that aging potentially changes the quantity and quality of MSC. Moreover, in this study, we investigated the capacity of the microenvironment [i.e., extracellular matrix (ECM)] to rescue the impaired proliferative and osteogenic potential of aged MSC. In this context, we aimed to understand if BM MSC features could be modulated by exposure to an ECM derived from cells obtained from young or old donors. When aged MSC were cultured on decellularized ECM derived from young MSC, their in vitro proliferative and osteogenic capacities were enhanced, which did not happen when cultured on old ECM. Our results suggest that the microenvironment, specifically the ECM, plays a crucial role in the quality (assessed in terms of osteogenic differentiation capacity) and quantity of MSC. Specifically, the aging of ECM is determinant of osteogenic differentiation of MSC. In fact, old MSC maintained on a young ECM produced higher amounts of extracellularly deposited calcium (9.10 ± 0.22 vs. 4.69 ± 1.41 μg.μl–1.10–7 cells for young ECM and old ECM, respectively) and up-regulated the expression of osteogenic gene markers such as Runx2 and OPN. Cell rejuvenation by exposure to a functional ECM might be a valuable clinical strategy to overcome the age-related decline in the osteogenic potential of MSC by recapitulating a younger microenvironment, attenuating the effects of aging on the stem cell niche. Overall, this study provides new insights on the osteogenic potential of MSC during aging and opens new possibilities for developing clinical strategies for elderly patients with limited bone formation capacity who currently lack effective treatments.

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  • Older donors of BM-MSCs have lower osteogenic, adipogenic and neurogenic capacities.

    “with older donors of BM-MSCs having lower proliferation rates [246], [249] and osteogenic [246], [248], adipogenic and neurogenic [248] capacities.”

    From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [246]

    The Discussion reports reduced osteogenic capacity in BM-MSCs from older donors. The Results say cells from both age groups could differentiate into adipogenic lineages, but do not report lower adipogenic capacity in older donors; the paper does not address neurogenic capacity. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Donor age and sex can affect MSC activity and thus the properties of MSC-secretome.

    “In addition, the number of MSC passage [246], [247], [248] and the donor variability [246], [247], [248] cannot be ignored since MSC activity and, thus, the properties of MSC-secretome can be affected by donor age and sex [246], [248], [249]”

    From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [246]

    The Discussion reports that older donors’ MSC had reduced proliferative and osteogenic capacities and suggests that aging may alter MSC-derived extracellular matrix. The paper does not establish an effect of donor sex or assess the broader MSC secretome; those parts of the attributed claim are unsupported. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Older donors of BM-MSCs have lower proliferation rates.

    “with older donors of BM-MSCs having lower proliferation rates [246], [249] and osteogenic [246], [248], adipogenic and neurogenic [248] capacities.”

    From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [246]

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Research works printed but not linked: 54

  1. Asumda F. Z. (2013). Age-associated changes in the ecological niche: implications for mesenchymal stem cell aging. Stem Cell Res. Ther. 4 47– 57. 10.1186/scrt197 23673056 PMC3706986 · DOI
  2. Baker N. Boyette L. B. Tuan R. S. (2015). Characterization of bone marrow-derived mesenchymal stem cells in aging. Bone 70 37– 47. 10.1016/j.bone.2014.10.014 25445445 · DOI
  3. Block T. J. Marinkovic M. Tran O. N. Gonzalez A. O. Marshall A. Dean D. D. (2017). Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies. Stem Cell Res. Ther. 8 239. 10.1186/s13287-017-0688-x 29078802 PMC5658952 · DOI
  4. Brownlee M. (1995). Advanced protein glycosylation in diabetes and aging. Annu. Rev. Med. 46 223– 234. 10.1146/annurev.med.46.1.223 7598459 · DOI · Paper page
  5. Byron A. Humphries J. D. Humphries M. J. (2013). Defining the extracellular matrix using proteomics. Int. J. Exp. Pathol. 94 75– 92. 10.1111/iep.12011 23419153 PMC3607136 · DOI
  6. Campisi J. Kapahi P. Lithgow G. J. Melov S. Newman J. C. Verdin E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature 571 183– 192. 10.1038/s41586-019-1365-2 31292558 PMC7205183 · DOI · Paper page
  7. Carlson M. E. Conboy I. M. (2007). Loss of stem cell regenerative capacity within aged niches. Aging Cell 6 371– 382. 10.1111/j.1474-9726.2007.00286.x 17381551 PMC2063610 · DOI
  8. Carvalho M. S. Silva J. C. Cabral J. M. S. da Silva C. L. Vashishth D. (2019b). Cultured cell-derived extracellular matrices to enhance the osteogenic differentiation and angiogenic properties of human mesenchymal stem/stromal cells. J. Tissue Eng. Regen. Med. 13 1544– 1558. 10.1002/term.2907 31151132 · DOI
  9. Carvalho M. S. Silva J. C. Udangawa R. N. Cabral J. M. S. Ferreira F. C. da Silva C. L. (2019c). Co-culture cell-derived extracellular matrix loaded electrospun microfibrous scaffolds for bone tissue engineering. Mater. Sci. Eng. C Mater. Biol. Appl. 99 479– 490. 10.1016/j.msec.2019.01.127 30889723 PMC6452855 · DOI
  10. Carvalho M. S. Cabral J. M. da Silva C. L. Vashishth D. (2019a). Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties. J. Cell. Biochem. 120 6555– 6569. 10.1002/jcb.27948 30362184 · DOI
  11. Carvalho M. S. Cabral J. M. S. da Silva C. L. Vashishth D. (2021). Bone matrix non-collagenous proteins in tissue engineering: creating new bone by mimicking the extracellular matrix. Polymers (Basel) 13: 1095. 10.3390/polym13071095 33808184 PMC8036283 · DOI
  12. Carvalho M. S. Poundarik A. A. Cabral J. M. S. da Silva C. L. Vashishth D. (2018). Biomimetic matrices for rapidly forming mineralized bone tissue based on stem cell-mediated osteogenesis. Sci. Rep. 8: 14388. 10.1038/s41598-018-32794-4 30258220 PMC6158243 · DOI
  13. Carvalho M. S. Silva J. C. Hoff C. M. Cabral J. M. S. Linhardt R. J. da Silva C. L. (2020). Loss and rescue of osteocalcin and osteopontin modulate osteogenic and angiogenic features of mesenchymal stem/stromal cells. J. Cell. Physiol. 235 7496– 7515. 10.1002/jcp.29653 32162324 · DOI
  14. Corrado A. Cici D. Rotondo C. Maruotti N. Cantatore F. P. (2020). Molecular basis of bone aging. Int. J. Mol. Sci. 21: 3679. 10.3390/ijms21103679 32456199 PMC7279376 · DOI
  15. DiLoreto R. Murphy C. T. (2015). The cell biology of aging. Mol. Biol. Cell 26 4524– 4531. 10.1091/mbc.E14-06-1084 26668170 PMC4678010 · DOI
  16. Dominici M. Le Blanc K. Mueller I. Slaper-Cortenbach I. Marini F. Krause D. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8 315– 317. 10.1080/14653240600855905 16923606 · DOI · Paper page
  17. Engler A. J. Sen S. Sweeney H. L. Discher D. E. (2006). Matrix elasticity directs stem cell lineage specification. Cell 126 677– 689. 10.1016/j.cell.2006.06.044 16923388 · DOI · Paper page
  18. Fafián-Labora J. A. Morente-López M. Arufe M. C. (2019). Effect of aging on behaviour of mesenchymal stem cells. World J. Stem Cells 11 337– 346. 10.4252/wjsc.v11.i6.337 31293716 PMC6600848 · DOI
  19. Fickert S. Schroter-Bobsin U. Gross A. F. Hempel U. Wojciechowski C. Rentsch C. (2010). Human mesenchymal stem cell proliferation and osteogenic differentiation during long-term ex vivo cultivation is not age dependent. J. Bone Miner. Metab. 29 224– 235. 10.1007/s00774-010-0215-y 20811759 · DOI
  20. Fuchs E. Tumbar T. Guasch G. (2004). Socializing with the neighbors: stem cells and their niche. Cell 116 769– 778. 10.1016/s0092-8674(04)00255-7 15035980 · DOI
  21. Ganguly P. El-Jawhari J. J. Giannoudis P. V. Burska A. N. Ponchel F. Jones E. A. (2017). Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transplant. 26 1520– 1529. 10.1177/0963689717721201 29113463 PMC5680949 · DOI
  22. Gattazzo F. Urciuolo A. Bonaldo P. (2014). Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim. Biophys. Acta 1840 2506– 2519. 10.1016/j.bbagen.2014.01.010 24418517 PMC4081568 · DOI
  23. Hoshiba T. Cho C. S. Murakawa A. Okahata Y. Akaike T. (2006). The effect of natural extracellular matrix deposited on synthetic polymers on cultured primary hepatocytes. Biomaterials 27 4519– 4528. 10.1016/j.biomaterials.2006.04.014 16697038 · DOI
  24. Hoshiba T. Lu H. Kawazoe N. Chen G. (2010). Decellularized matrices for tissue engineering. Expert Opin. Biol. Ther. 10 1717– 1728. 10.1517/14712598.2010.534079 21058932 · DOI
  25. Huang C. C. Jiang C. C. Hsieh C. H. Tsai C. J. Chiang H. (2016). Local bone quality affects the outcome of prosthetic total knee arthroplasty. J. Orthop. Res. 34 240– 248. 10.1002/jor.23003 26222735 · DOI
  26. Kirkwood T. B. (2005). Understanding the odd science of aging. Cell 120 437– 447. 10.1016/j.cell.2005.01.027 15734677 · DOI · Paper page
  27. Kornicka K. Marycz K. Tomaszewski K. A. Marȩdziak M. Śmieszek A. (2015). The effect of age on osteogenic and adipogenic differentiation potential of human adipose derived stromal stem cells (hASCs) and the impact of stress factors in the course of the differentiation process. Oxid. Med. Cell Longev. 2015: 309169. 10.1155/2015/309169 26246868 PMC4515302 · DOI
  28. Kurtz A. Oh S. J. (2012). Age related changes of the extracellular matrix and stem cell maintenance. Prev. Med. 54 S50– S56. 10.1016/j.ypmed.2012.01.003 22285947 · DOI
  29. Lai Y. Sun Y. Skinner C. M. Son E. L. Lu Z. Tuan R. S. (2010). Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. Stem Cells Dev. 19 1095– 1107. 10.1089/scd.2009.0217 19737070 PMC3128312 · DOI
  30. Li Y. Wu Q. Wang Y. Li L. Bu H. Bao J. (2017). Senescence of mesenchymal stem cells (review). Int. J. Mol. Med. 39 775– 782. 10.3892/ijmm.2017.2912 28290609 · DOI
  31. Liao J. Guo X. Grande-Allen K. J. Kasper F. K. Mikos A. G. (2010). Bioactive polymer/extracellular matrix scaffolds fabricated with a flow perfusion bioreactor for cartilage tissue engineering. Biomaterials 31 8911– 8920. 10.1016/j.biomaterials.2010.07.110 20797784 PMC2953640 · DOI
  32. Lin H. Yang G. Tan J. Tuan R. S. (2012). Influence of decellularized matrix derived from human mesenchymal stem cells on their proliferation, migration and multi-lineage differentiation potential. Biomaterials 33 4480– 4489. 10.1016/j.biomaterials.2012.03.012 22459197 · DOI · Paper page
  33. Lindner U. Kramer J. Behrends J. Driller B. Wendler N. O. Boehrnsen F. (2010). Improved proliferation and differentiation capacity of human mesenchymal stromal cells cultured with basement-membrane extracellular matrix proteins. Cytotherapy 12 992– 1005. 10.3109/14653249.2010.510503 20807021 · DOI
  34. Liu A. P. Chaudhuri O. Parekh S. H. (2017). New advances in probing cell-extracellular matrix interactions. Integr. Biol. (Camb.). 9 383– 405. 10.1039/c6ib00251j 28352896 PMC5708530 · DOI
  35. Liu J. Ding Y. Liu Z. Liang X. (2020). Senescence in mesenchymal stem cells: functional alterations, molecular mechanisms, and rejuvenation strategies. Front. Cell. Dev. Biol. 8: 258. 10.3389/fcell.2020.00258 32478063 PMC7232554 · DOI
  36. Moore K. A. Lemischka I. R. (2006). Stem cells and their niches. Science 311 1880– 1885. 10.1126/science.1110542 16574858 · DOI
  37. Mueller S. M. Glowacki J. (2001). Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J. Cell. Biochem. 82 583– 590. 10.1002/jcb.1174 11500936 · DOI
  38. Nicolas J. Magli S. Rabbachin L. Sampaolesi S. Nicotra F. Russo L. (2020). 3D extracellular matrix mimics: fundamental concepts and role of materials chemistry to influence stem cell fate. Biomacromolecules 8 1968– 1994. 10.1021/acs.biomac.0c00045 32227919 · DOI · Paper page
  39. Novoseletskaya E. Grigorieva O. Nimiritsky P. Basalova N. Eremichev R. Milovskaya I. (2020). Mesenchymal stromal cell-produced components of extracellular matrix potentiate multipotent stem cell response to differentiation stimuli. Front. Cell. Dev. Biol. 8: 555378. 10.3389/fcell.2020.555378 33072743 PMC7536557 · DOI · Paper page
  40. Payr S. Schuseil T. Unger M. Seeliger C. Tiefenboeck T. Balmayor E. R. (2020). Effect of donor age and 3D-cultivation on osteogenic differentiation capacity of adipose-derived mesenchymal stem cells. Sci. Rep. 10: 13184. 10.1038/s41598-020-67254-5 32737385 PMC7395092 · DOI
  41. Pignolo R. J. Law S. F. Chandra A. (2021). Bone aging, cellular senescence, and osteoporosis. JBMR Plus 5: e10488. 10.1002/jbm4.10488 33869998 PMC8046105 · DOI
  42. Pittenger M. F. Discher D. E. Péault B. M. Phinney D. G. Hare J. M. Caplan A. I. (2019). Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen. Med. 4: 22. 10.1038/s41536-019-0083-6 31815001 PMC6889290 · DOI · Paper page
  43. Pittenger M. F. Mackay A. M. Beck S. C. Jaiswal R. K. Douglas R. Mosca J. D. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284 143– 147. 10102814
  44. Rapp A. E. Bindl R. Erbacher A. Kruchen A. Rojewski M. Schrezenmeier H. (2018). Autologous mesenchymal stroma cells are superior to allogeneic ones in bone defect regeneration. Int. J. Mol. Sci. 19: 2526. 10.3390/ijms19092526 30149650 PMC6163925 · DOI
  45. Schmitt A. van Griensven M. Imhoff A. B. Buchmann S. (2012). Application of stem cells in orthopedics. Stem Cells Int. 2012: 394962. 10.1155/2012/394962 22550505 PMC3328166 · DOI
  46. Sethe S. Scutt A. Stolzing A. (2006). Aging of mesenchymal stem cells. Ageing Res. Rev. 5 91– 116. 10.1016/j.arr.2005.10.001 16310414 · DOI
  47. Silva J. C. Carvalho M. S. Han X. Xia K. Mikael P. E. Cabral J. M. S. (2019). Compositional and structural analysis of glycosaminoglycans in cell-derived extracellular matrices. Glycoconj. J. 36 141– 154. 10.1007/s10719-019-09858-2 30637588 PMC6487206 · DOI
  48. Silva J. C. Carvalho M. S. Udangawa R. N. Moura C. S. Cabral J. M. S. da Silva C. L. (2020). Extracellular matrix decorated polycaprolactone scaffolds for improved mesenchymal stem/stromal cell osteogenesis towards a patient-tailored bone tissue engineering approach. J. Biomed. Mater. Res. B Appl. Biomater. 108 2153– 2166. 10.1002/jbm.b.34554 31916699 · DOI
  49. Song J. J. Ott H. C. (2011). Organ engineering based on decellularized matrix scaffolds. Trends Mol. Med. 17 424– 432. 10.1016/j.molmed.2011.03.005 21514224 · DOI · Paper page
  50. Stenderup K. Justesen J. Clausen C. Kassem M. (2003). Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33 919– 926. 10.1016/j.bone.2003.07.005 14678851 · DOI
  51. Stolzing A. Scutt A. (2006). Age-related impairment of mesenchymal progenitor cell function. Aging Cell 5 213– 224. 10.1111/j.1474-9726.2006.00213.x 16842494 · DOI
  52. Sun Y. Li W. Lu Z. Chen R. Ling J. Ran Q. (2011). Rescuing replication and osteogenesis of aged mesenchymal stem cells by exposure to a young extracellular matrix. FASEB J. 25 1474– 1485. 10.1096/fj.10-161497 21248241 PMC3079301 · DOI
  53. Thibault M. M. Hoemann C. D. Buschmann M. D. (2007). Fibronectin, vitronectin, and collagen I induce chemotaxis and haptotaxis of human and rabbit mesenchymal stem cells in a standardized transmembrane assay. Stem Cells Dev. 16 489– 502. 10.1089/scd.2006.0100 17610379 · DOI
  54. Vester H. Huber-Lang M. S. Kida Q. Scola A. van Griensven M. Gebhard F. (2014). The immune response after fracture trauma is different in old compared to young patients. Immun. Ageing 11: 20. 10.1186/s12979-014-0020-x 25620994 PMC4305233 · DOI

Cited by

Sorted by citations

Authors
Carvalho, M. S., Alves, L., Bogalho, I., Cabral, J. M. S., & da Silva, C. L.
Affiliations
University of Lisbon (PT)
Corresponding author
Carvalho, Marta S.
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2021-10-05
Volume
9
Pages
747521-747521
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2021.747521
PMC
PMC8523799
OpenAlex
W3202254670
Cited by
61
References
3
Citations by year
2026: 10 · 2025: 14 · 2024: 15 · 2023: 13 · 2022: 9
FWCI
5.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fundação para a Ciência e a Tecnologia (PTDC/BTM-BTM/3538/2020)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
mesenchymal stem cells, donor age, aging, extracellular matrix, decellularized extracellular matrix, osteogenic differentiation, bone marrow, cellular rejuvenation, stem cell niche, fracture healing, Runx2, osteopontin, cell proliferation

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