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Nyström, M., Lauvrud, A.-T., Pérez-Díaz, S., Kingham, P. J. & Wiberg, R. (2023). Interaction of adipose-derived stem cells with active and dormant breast cancer cells. Paper presented at Scandinavian Association of Plastic Surgeons Congress, Reykjavik, Iceland, June 13–15, 2022. Journal of Plastic, Reconstructive & Aesthetic Surgery, 83, 69-76
Open this publication in new window or tab >>Interaction of adipose-derived stem cells with active and dormant breast cancer cells
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2023 (English)In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1878-0539, Vol. 83, p. 69-76Article in journal (Refereed) Published
Abstract [en]

Background: Although autologous fat grafting is considered a successful method for the management of contour deformities, the fat graft could potentially induce cancer reappearance by fueling dormant breast cancer cells. Our aim was to characterize the role of adipose-derived stem cells on active and dormant breast cancer cell growth.

Methods: Cobalt chloride was used to induce dormancy in MCF-7 cancer cells. Proliferation of active and dormant cancer cells was determined in the presence of adipose-derived stem cells. A proteome array was used to detect cancer-related protein expression in the cell-conditioned medium. The migration of cancer cells was measured in response to conditioned medium from the adipose-derived stem cells.

Results: The adipose-derived stem cells showed variable effects on active MCF-7 cells growth and inhibited MCF-7 proliferation after the withdrawal of cobalt chloride. Of the 84 different proteins measured in the conditioned medium, only tenascin-C was differentially expressed in the co-cultures. MCF-7 cells alone did not express tenascin-C, whereas co-cultures between MCF-7 and adipose-derived stem cells expressed more tenascin-C versus adipose-derived stem cells alone. The conditioned medium from co-cultures significantly increased the migration of the cancer cells.

Conclusions: Adipose-derived stem cells themselves neither increased the growth or migration of cancer cells, suggesting that autologous fat grafting may be oncologically safe if reconstruction is postponed until there is no evidence of active disease. However, interactions between adipose-derived stem cells and MCF-7 cancer cells could potentially lead to the production of factors, which further promote cancer cell migration.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Adipose-derived stem cells (ASCs), Autologous fat grafting (AFG), Dormant breast cancer cells, Tenascin-C
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-209546 (URN)10.1016/j.bjps.2023.05.006 (DOI)001020879400001 ()37270997 (PubMedID)2-s2.0-85160658685 (Scopus ID)
Conference
Scandinavian Association of Plastic Surgeons Congress, Reykjavik, Iceland, June 13–15, 2022
Funder
Umeå UniversityRegion Västerbotten
Available from: 2023-06-13 Created: 2023-06-13 Last updated: 2024-01-26Bibliographically approved
Anerillas, L. O., Wiberg, M., Kingham, P. J. & Kelk, P. (2023). Platelet lysate for expansion or osteogenic differentiation of bone marrow mesenchymal stem cells for 3D tissue constructs. Regenerative Therapy, 24, 298-310
Open this publication in new window or tab >>Platelet lysate for expansion or osteogenic differentiation of bone marrow mesenchymal stem cells for 3D tissue constructs
2023 (English)In: Regenerative Therapy, E-ISSN 2352-3204, Vol. 24, p. 298-310Article in journal (Refereed) Published
Abstract [en]

Background: The use of mesenchymal stem cells (MSCs) for the development of tissue-engineered constructs has advanced in recent years. However, future clinically approved products require following good manufacturing practice (GMP) guidelines. This includes using alternatives to xenogeneic-derived cell culture supplements to avoid rejection of the transplants. Consequently, human platelet lysate (PLT) has been adopted as an affordable and effective alternative to foetal bovine serum (FBS) in traditional 2D cultures. However, little is known about its effect in more advanced 3D culture systems.

Methods: We evaluated bone marrow MSCs (BMSCs) proliferation and CD marker expression in cells expanded in FBS or PLT-supplemented media. Differentiation capacity of the BMSCs expanded in the presence of the different supplements was evaluated in 3D type I collagen hydrogels. Furthermore, the effects of the supplements on the process of differentiation were analyzed by using qPCR and histological staining.

Results: Cell proliferation was greater in PLT-supplemented media versus FBS. BMSCs expanded in PLT showed similar osteogenic differentiation capacity in 3D compared with FBS expanded cells. In contrast, when cells were 3D differentiated in PLT they showed lower osteogenesis versus the traditional FBS protocol. This was also the case for adipogenic differentiation, in which FBS supplementation was superior to PLT.

Conclusions: PLT is a superior alternative to FBS for the expansion of MSCs without compromising their subsequent differentiation capacity in 3D. However, differentiation in PLT is impaired. Thus, PLT can be used to reduce the time required to expand the necessary cell numbers for development of 3D tissue engineered MSC constructs.

Place, publisher, year, edition, pages
Japanese Society of Regenerative Medicine, 2023
Keywords
3D, Foetal bovine serum, Human platelet lysate, Mesenchymal stem cells, Osteogenesis
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-213420 (URN)10.1016/j.reth.2023.07.011 (DOI)37588134 (PubMedID)2-s2.0-85167829822 (Scopus ID)
Funder
Region Västerbotten, 7003459Region Västerbotten, 7003589Umeå University
Available from: 2023-08-25 Created: 2023-08-25 Last updated: 2023-11-20Bibliographically approved
Li, J., Zhou, X., Chen, J., Eliasson, P., Kingham, P. J. & Backman, L. J. (2023). Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway. The FASEB Journal, 37(10), Article ID e23203.
Open this publication in new window or tab >>Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway
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2023 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 37, no 10, article id e23203Article in journal (Refereed) Published
Abstract [en]

Exercise is widely recognized as beneficial for tendon healing. Recently, it has been described that muscle-derived molecules secreted in response to static exercise influence tendon healing. In this study, the optimal static loading intensity for tendon healing and the composition of secretome released by myoblasts in response to different intensities of static strain were investigated. In an in vitro coculture model, myoblasts were mechanically loaded using a Flexcell Tension System. Tenocytes were seeded on transwell inserts that allowed communication between the tenocytes and myoblasts without direct contact. Proliferation and migration assays, together with RNA sequencing, were used to determine potential cellular signaling pathways. The secretome from myoblasts exposed to 2% static loading increased the proliferation and migration of the cocultured tenocytes. RNA-seq analysis revealed that this loading condition upregulated the expression of numerous genes encoding secretory proteins, including insulin-like growth factor-1 (IGF-1). Confirmation of IGF-1 expression and secretion was carried out using qPCR and enzyme-linked immunosorbt assay (ELISA), revealing a statistically significant upregulation in response to 2% static loading in comparison to both control conditions and higher loading intensities of 5% and 10%. Addition of an inhibitor of the IGF-1 receptor (PQ401) to the tenocytes significantly reduced myoblast secretome-induced tenocyte proliferation. In conclusion, IGF-1 may be an important molecule in the statically loaded myoblast secretome, which is responsible for influencing tenocytes during exercise-induced healing.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
IGF-1, mechanical loading, migration, muscle secretome, proliferation, tenocyte
National Category
Cell and Molecular Biology Physiotherapy
Identifiers
urn:nbn:se:umu:diva-214756 (URN)10.1096/fj.202301097R (DOI)37732638 (PubMedID)2-s2.0-85171800001 (Scopus ID)
Funder
Åke Wiberg Foundation, M20-0236Åke Wiberg Foundation, M22-0008The Kempe Foundations, JCK- 2032.2Swedish National Centre for Research in Sports, P2022-0010Swedish National Centre for Research in Sports, P2023-0011
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18Bibliographically approved
Thomson, S. E., Ng, N. Y. .., Riehle, M. O., Kingham, P. J., Dahlin, L. B., Wiberg, M. & Hart, A. M. (2022). Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb. Cochrane Database of Systematic Reviews (12), Article ID CD012574.
Open this publication in new window or tab >>Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb
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2022 (English)In: Cochrane Database of Systematic Reviews, ISSN 1469-493X, E-ISSN 1469-493X, no 12, article id CD012574Article, review/survey (Refereed) Published
Abstract [en]

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and compare the effects and complication rates of licensed bioengineered nerve conduits or wraps for surgical repair of traumatic peripheral nerve injuries of the upper limb. To compare effects and complications against the current gold surgical standard (nerve autograft).

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-202649 (URN)10.1002/14651858.CD012574.pub2 (DOI)000949395500013 ()36477774 (PubMedID)2-s2.0-85143554403 (Scopus ID)
Available from: 2023-01-16 Created: 2023-01-16 Last updated: 2023-12-05Bibliographically approved
Kumar Kuna, V., Lundgren, A., Anerillas, L. O., Kelk, P., Brohlin, M., Wiberg, M., . . . Novikov, L. N. (2022). Efficacy of Nerve-Derived Hydrogels to Promote Axon Regeneration Is Influenced by the Method of Tissue Decellularization. International Journal of Molecular Sciences, 23(15), Article ID 8746.
Open this publication in new window or tab >>Efficacy of Nerve-Derived Hydrogels to Promote Axon Regeneration Is Influenced by the Method of Tissue Decellularization
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2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, article id 8746Article in journal (Refereed) Published
Abstract [en]

Injuries to large peripheral nerves are often associated with tissue defects and require reconstruction using autologous nerve grafts, which have limited availability and result in donor site morbidity. Peripheral nerve-derived hydrogels could potentially supplement or even replace these grafts. In this study, three decellularization protocols based on the ionic detergents sodium dodecyl sulfate (P1) and sodium deoxycholate (P2), or the organic solvent tri-n-butyl phosphate (P3), were used to prepare hydrogels. All protocols resulted in significantly decreased amounts of genomic DNA, but the P2 hydrogel showed the best preservation of extracellular matrix proteins, cytokines, and chemokines, and reduced levels of sulfated glycosaminoglycans. In vitro P1 and P2 hydrogels supported Schwann cell viability, secretion of VEGF, and neurite outgrowth. Surgical repair of a 10 mm-long rat sciatic nerve gap was performed by implantation of tubular polycaprolactone conduits filled with hydrogels followed by analyses using diffusion tensor imaging and immunostaining for neuronal and glial markers. The results demonstrated that the P2 hydrogel considerably increased the number of axons and the distance of regeneration into the distal nerve stump. In summary, the method used to decellularize nerve tissue affects the efficacy of the resulting hydrogels to support regeneration after nerve injury.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
MRI, biosynthetic conduit, decellularized nerve tissue, diffusion tensor imaging, nerve-derived hydrogel, peripheral nerve injury
National Category
Neurosciences Surgery Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-199043 (URN)10.3390/ijms23158746 (DOI)000839268700001 ()35955880 (PubMedID)2-s2.0-85137098673 (Scopus ID)
Funder
Region VästerbottenVinnova, 2017-02130
Available from: 2022-09-01 Created: 2022-09-01 Last updated: 2022-10-03Bibliographically approved
Schaakxs, D., Wiberg, M., Kingham, P. J. & Kalbermatten, D. F. (2022). Intramuscular Stem Cell Injection in Combination with Bioengineered Nerve Repair or Nerve Grafting Reduces Muscle Atrophy. Plastic and reconstructive surgery (1963), 149(5), 905E-913E
Open this publication in new window or tab >>Intramuscular Stem Cell Injection in Combination with Bioengineered Nerve Repair or Nerve Grafting Reduces Muscle Atrophy
2022 (English)In: Plastic and reconstructive surgery (1963), ISSN 0032-1052, E-ISSN 1529-4242, Vol. 149, no 5, p. 905E-913EArticle in journal (Refereed) Published
Abstract [en]

Background: Peripheral nerve injuries represent a clinical challenge, especially when they are accompanied by loss of neural tissue. In this study, the authors attempted to attain a better outcome after a peripheral nerve injury by both repairing the nerve lesion and treating the denervated muscle at the same time.

Methods: Rat sciatic nerves were transected to create 10-mm gaps. Repair was performed in five groups (n = 5 rats for each), as follows: group 1, nerve repair using poly-3-hydroxybutyrate strips to connect the proximal and distal stumps, in combination with control growth medium injection in the gastrocnemius muscle; group 2, nerve repair with poly-3-hydroxybutyrate strip seeded with Schwann cell-like differentiated adipose stem cells (differentiated adipose stem cell strip) in combination with growth medium intramuscular injection; group 3, differentiated adipose stem cell strip in combination with intramuscular injection of differentiated adipose stem cells; group 4, repair using autograft (reverse sciatic nerve graft) in combination with intramuscular injection of growth medium; and group 5, autograft in combination with intramuscular injection of differentiated adipose stem cells. Six weeks after nerve injury, the effects of the stem cells on muscle atrophy were assessed.

Results: Poly-3-hydroxybutyrate strips seeded with differentiated adipose stem cells showed a high number of βIII-tubulin-positive axons entering the distal stump and abundant endothelial cells. Group 1 animals exhibited more muscle atrophy than all the other groups, and group 5 animals had the greatest muscle weights and muscle fibers size.

Conclusion: Bioengineering nerve repair in combination with intramuscular stem cell injection is a promising technique to treat nerve lesions and associated muscle atrophy. Clinical Relevance Statement: Nerve injuries and resulting muscle atrophy are a clinical challenge. To optimize functional recovery after a nerve lesion, the authors treated the nerve and muscle at the same time by using regenerative medicine with adipose stem cells and obtained encouraging results for future clinical applications.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2022
National Category
Surgery Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-194883 (URN)10.1097/PRS.0000000000009031 (DOI)000788119300008 ()35271540 (PubMedID)2-s2.0-85129244800 (Scopus ID)
Funder
Swedish Research CouncilEU, European Research CouncilRegion Västerbotten
Available from: 2022-06-07 Created: 2022-06-07 Last updated: 2023-05-09Bibliographically approved
El-Habta, R., Andersson, G., Kingham, P. J. & Backman, L. J. (2021). Anti-apoptotic effect of adipose tissue-derived stromal vascular fraction in denervated rat muscle. Stem Cell Research & Therapy, 12(162)
Open this publication in new window or tab >>Anti-apoptotic effect of adipose tissue-derived stromal vascular fraction in denervated rat muscle
2021 (English)In: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 12, no 162Article in journal (Refereed) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-169728 (URN)10.1186/s13287-021-02230-y (DOI)000626520900001 ()2-s2.0-85102009955 (Scopus ID)
Available from: 2020-04-20 Created: 2020-04-20 Last updated: 2023-09-05Bibliographically approved
Kumar Kuna, V. & Kingham, P. J. (2021). Peripheral nerve tissue engineering (3ed.). In: Aldo R. Boccaccini; Peter X. Ma; Liliana Liverani (Ed.), Tissue engineering using ceramics and polymers: (pp. 481-517). Duxford: Woodhead Publishing Limited
Open this publication in new window or tab >>Peripheral nerve tissue engineering
2021 (English)In: Tissue engineering using ceramics and polymers / [ed] Aldo R. Boccaccini; Peter X. Ma; Liliana Liverani, Duxford: Woodhead Publishing Limited, 2021, 3, p. 481-517Chapter in book (Refereed)
Abstract [en]

Peripheral nerve injury is a frequent clinical problem and causes loss of motor and sensory functions for patients. Though some inherent regeneration capacity exists, this is often very limited in the cases of nerve tissue gaps. The design of a nerve conduit that results in successful nerve axon regeneration across these gaps and recovery of normal functions is a significant challenge for researchers in the fields of tissue engineering and regenerative medicine. This chapter includes a historic background to this research area and summarizes the current knowledge of various biomaterials, fabrication techniques and structural modifications, and the inclusion of cell and molecular therapies used in the production of nerve conduits.

Place, publisher, year, edition, pages
Duxford: Woodhead Publishing Limited, 2021 Edition: 3
Series
Woodhead Publishing Series in Biomaterials
Keywords
Biomaterials, Cell and molecular therapy, Hydrogel, Nerve conduit, Peripheral nerve, Regeneration
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-201258 (URN)10.1016/B978-0-12-820508-2.00006-4 (DOI)2-s2.0-85141293855 (Scopus ID)9780128205082 (ISBN)9780128205792 (ISBN)
Available from: 2022-12-05 Created: 2022-12-05 Last updated: 2022-12-13Bibliographically approved
Zhou, X., Li, J., Giannopoulos, A., Kingham, P. J. & Backman, L. J. (2021). Secretome from in vitro mechanically loaded myoblasts induces tenocyte migration, transition to a fibroblastic phenotype and suppression of collagen production. International Journal of Molecular Sciences, 22(23), Article ID 13089.
Open this publication in new window or tab >>Secretome from in vitro mechanically loaded myoblasts induces tenocyte migration, transition to a fibroblastic phenotype and suppression of collagen production
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 23, article id 13089Article in journal (Refereed) Published
Abstract [en]

It is known that mechanical loading of muscles increases the strength of healing tendon tissue, but the mechanism involved remains elusive. We hypothesized that the secretome from myoblasts in co-culture with tenocytes affects tenocyte migration, cell phenotype, and collagen (Col) production and that the effect is dependent on different types of mechanical loading of myoblasts. To test this, we used an in vitro indirect transwell co-culture system. Myoblasts were mechanically loaded using the FlexCell® Tension system. Tenocyte cell migration, proliferation, apoptosis, collagen production, and several tenocyte markers were measured. The secretome from myoblasts decreased the Col I/III ratio and increased the expression of tenocyte specific markers as compared with tenocytes cultured alone. The secretome from statically loaded myoblasts significantly enhanced tenocyte migration and Col I/III ratio as compared with dynamic loading and controls. In addition, the secretome from statically loaded myoblasts induced tenocytes towards a myofibroblast-like phenotype. Taken together, these results demonstrate that the secretome from statically loaded myoblasts has a profound influence on tenocytes, affecting parameters that are related to the tendon healing process.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Collagen, Differentiation, Mechanical loading, Migration, Myoblast, Proliferation, Secretome, Tenocyte
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-190287 (URN)10.3390/ijms222313089 (DOI)000735301000001 ()2-s2.0-85120611428 (Scopus ID)
Available from: 2021-12-13 Created: 2021-12-13 Last updated: 2023-10-18Bibliographically approved
Anerillas, L. O., Kingham, P. J., Lammi, M., Wiberg, M. & Kelk, P. (2021). Three-dimensional osteogenic differentiation of bone marrow mesenchymal stem cells promotes matrix metallopeptidase 13 (Mmp13) expression in type i collagen hydrogels. International Journal of Molecular Sciences, 22(24), Article ID 13594.
Open this publication in new window or tab >>Three-dimensional osteogenic differentiation of bone marrow mesenchymal stem cells promotes matrix metallopeptidase 13 (Mmp13) expression in type i collagen hydrogels
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 24, article id 13594Article in journal (Refereed) Published
Abstract [en]

Autologous bone transplantation is the principal method for reconstruction of large bone defects. This technique has limitations, such as donor site availability, amount of bone needed and morbidity. An alternative to this technique is tissue engineering with bone marrow-derived mesenchymal stem cells (BMSCs). In this study, our aim was to elucidate the benefits of culturing BMSCs in 3D compared with the traditional 2D culture. In an initial screening, we combined BMSCs with four different biogels: unmodified type I collagen (Col I), type I collagen methacrylate (ColMa), an alginate and cellulose-based bioink (CELLINK) and a gelatin-based bioink containing xanthan gum (GelXA-bone). Col I was the best for structural integrity and maintenance of cell morphology. Osteogenic, adipogenic, and chondrogenic differentiations of the BMSCs in 2D versus 3D type I collagen gels were investigated. While the traditional pellet culture for chondrogenesis was superior to our tested 3D culture, Col I hydrogels (i.e., 3D) favored adipogenic and osteogenic differentiation. Further focus of this study on osteogenesis were conducted by comparing 2D and 3D differentiated BMSCs with Osteoimage® (stains hydroxyapatite), von Kossa (stains anionic portion of phosphates, carbonates, and other salts) and Alizarin Red (stains Ca2+ deposits). Multivariate gene analysis with various covariates showed low variability among donors, successful osteogenic differentiation, and the identification of one gene (matrix metallopeptidase 13, MMP13) significantly differentially expressed in 2D vs. 3D cultures. MMP13 protein expression was confirmed with immunohistochemistry. In conclusion, this study shows evidence for the suitability of type I collagen gels for 3D osteogenic differentiation of BMSCs, which might improve the production of tissue-engineered constructs for treatment of bone defects.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
3D culture, Biogel, Cell differentiation, Mesenchymal stem cells, MMP13, MSCs, Osteogenesis, Type I collagen
National Category
Medical Materials
Identifiers
urn:nbn:se:umu:diva-190846 (URN)10.3390/ijms222413594 (DOI)000737916100001 ()2-s2.0-85121319833 (Scopus ID)
Available from: 2021-12-29 Created: 2021-12-29 Last updated: 2023-11-20Bibliographically approved
Projects
Centre for Advanced Medical Products [2017-02130_Vinnova]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2596-5936

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