Caplan H, et al. Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol. 2019;10:1645.

CAS  PubMed  PubMed Central  Google Scholar 

Moll G, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019;25(2):149–63.

PubMed  Google Scholar 

Zhao K, et al. Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(1):97–104.

CAS  PubMed  Google Scholar 

Kurtzberg J, et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014;20(2):229–35.

PubMed  Google Scholar 

Moon K-C, et al. Potential of allogeneic adipose-derived stem cell-hydrogel complex for treating diabetic foot ulcers. Diabetes (New York, N.Y.). 2019;68(4):837–846

Lin Bl, et al. Allogeneic bone marrow–derived mesenchymal stromal cells for hepatitis B virus–related acute‐on‐chronic liver failure: A randomized controlled trial. Hepatology (Baltimore, Md.). 2017;66(1):209–219.

Petrou P, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain (London, England : 1878). 2020;143(12):3574–3588.

Allen A, et al. Mesenchymal Stromal Cell Bioreactor for Ex Vivo Reprogramming of Human Immune Cells. Sci Rep. 2020;10(1):10142.

CAS  PubMed  PubMed Central  Google Scholar 

•• Swaminathan M, et al. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med. 2021. This study reports a pharmacokinetic/pharmacodynamic response in human patients with systemic inflammatory diseases that are treated by ex vivo MSC therapy.

van Poll D, et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47(5):1634–43.

PubMed  Google Scholar 

• Olsen TR, et al. Peak MSC-Are we there yet? Front Med. 2018;5:178–178. This review captures critical process development goals under a target product profile for commercial, allogeneic MSC products.

Google Scholar 

François M, et al. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. 2012;20(1):187–95.

PubMed  Google Scholar 

Moll G, et al. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014;32(9):2430–42.

CAS  PubMed  PubMed Central  Google Scholar 

Smith D, et al. Towards automated manufacturing for cell therapies. Curr Hematol Malig Rep. 2019;14(4):278–85.

PubMed  Google Scholar 

Siegel G, et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 2013;11(1):146–146.

CAS  PubMed  PubMed Central  Google Scholar 

Heathman TRJ, et al. Characterization of human mesenchymal stem cells from multiple donors and the implications for large scale bioprocess development. Biochem Eng J. 2016;108:14–23.

CAS  Google Scholar 

Andrzejewska A, et al. Multi-parameter analysis of biobanked human bone marrow stromal cells shows little influence for donor age and mild comorbidities on phenotypic and functional properties. Front Immunol. 2019;10:2474.

CAS  PubMed  PubMed Central  Google Scholar 

Ikebe C, Suzuki K. Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols. Biomed Res Int. 2014;2014:951512–611.

PubMed  PubMed Central  Google Scholar 

Yin JQ, Zhu J, Ankrum JA. Manufacturing of primed mesenchymal stromal cells for therapy. Nature biomedical engineering. 2019;3(2):90–104.

CAS  PubMed  Google Scholar 

Drela K, et al. Bone marrow-derived from the human femoral shaft as a new source of mesenchymal stem/stromal cells: an alternative cell material for banking and clinical transplantation. Stem Cell Res Ther. 2020;11(1):1–262.

Google Scholar 

Lechanteur C, et al. Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J Transl Med. 2016;14(1):145.

PubMed  PubMed Central  Google Scholar 

Heathman TRJ, et al. Serum-free process development: improving the yield and consistency of human mesenchymal stromal cell production. Cytotherapy (Oxford, England). 2015;17(11):1524–35.

CAS  Google Scholar 

Capelli C, et al. Human platelet lysate allows expansion and clinical grade production of mesenchymal stromal cells from small samples of bone marrow aspirates or marrow filter washouts. Bone marrow transplantation (Basingstoke). 2007;40(8):785–91.

CAS  Google Scholar 

Bhat S, et al. Expansion and characterization of bone marrow derived human mesenchymal stromal cells in serum-free conditions. Sci Rep. 2021;11(1):3403–3403.

CAS  PubMed  PubMed Central  Google Scholar 

Rowley J, Abraham E, Campbell A, Brandwein H, Oh S. Meeting lot-size challenges of manufacturing adherent cells for therapy. BioProcess International. 2012;10(3):16–22.

CAS  Google Scholar 

Drzeniek NM, et al. Bio-instructive hydrogel expands the paracrine potency of mesenchymal stem cells. Biofabrication. 2021;13(4).

Matsiko A, Gleeson JP, O’Brien FJ. Scaffold mean pore size influences mesenchymal stem cell chondrogenic differentiation and matrix deposition. Tissue Eng Part A. 2015;21(3–4):486–97.

CAS  PubMed  Google Scholar 

de Almeida Fuzeta M, et al. Addressing the manufacturing challenges of cell-based therapies. Current Applications of Pharmaceutical Biotechnology. 2019;171:225–78.

Google Scholar 

Vymetalova L, et al. Large-scale automated hollow-fiber bioreactor expansion of umbilical cord-derived human mesenchymal stromal cells for neurological disorders. Neurochem Res. 2020;45(1):204–14.

CAS  PubMed  Google Scholar 

Lambrechts T, et al. Large-scale progenitor cell expansion for multiple donors in a monitored hollow fibre bioreactor. Cytotherapy (Oxford, England). 2016;18(9):1219–33.

CAS  Google Scholar 

Mizukami A, et al. A fully-closed and automated hollow fiber bioreactor for clinical-grade manufacturing of human mesenchymal stem/stromal cells. Stem cell reviews and reports. 2018;14(1):141–3.

CAS  PubMed  Google Scholar 

Haack-Sørensen M, et al. Culture expansion of adipose derived stromal cells. A closed automated Quantum Cell Expansion System compared with manual flask-based culture. J translational med. 2016;14(1):319–319.

Odeleye AOO, et al. An additive manufacturing approach to bioreactor design for mesenchymal stem cell culture. Biochem Eng J. 2020;156.

Jossen V, et al. Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges. Appl Microbiol Biotechnol. 2018;102(9):3981–94.

CAS  PubMed  PubMed Central  Google Scholar 

Lembong J, et al. Bioreactor parameters for microcarrier-based human MSC expansion under xeno-free conditions in a vertical-wheel system. Bioengineering (Basel). 2020;7(3):73.

CAS  Google Scholar 

•• Lawson T, et al. Process development for expansion of human mesenchymal stromal cells in a 50L single-use stirred tank bioreactor. Biochem Eng J. 2017;120:49–62. This study first reports important process development studies in the production of human MSCs at a 50L scale using microcarrier culture.

CAS  Google Scholar 

Rafiq QA, et al. Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor. Biotech Lett. 2013;35(8):1233–45.

CAS  Google Scholar 

Jing D, et al. Growth kinetics of human mesenchymal stem cells in a 3-L single-use, stirred-tank bioreactor. Biopharm international. 2013;26(4):28.

CAS  Google Scholar 

Schnitzler AC, et al. Bioprocessing of human mesenchymal stem/stromal cells for therapeutic use: Current technologies and challenges. Biochem Eng J. 2016;108:3–13.

CAS  Google Scholar 

Qazi TH, et al. Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs. Biomaterials. 2017;140:103–14.

CAS  PubMed  Google Scholar 

Khayambashi P, et al. Hydrogel encapsulation of mesenchymal stem cells and their derived exosomes for tissue engineering. Int J Molecular Sci. 2021;22(2).

Rafiq QA, et al. Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors. Biotechnol J. 2016;11(4):473–86.

CAS  PubMed  PubMed Central  Google Scholar 

Leber J, et al. Microcarrier choice and bead-to-bead transfer for human mesenchymal stem cells in serum-containing and chemically defined media. Process Biochem. 1991;2017(59):255–65.

Google Scholar 

Jung S, et al. Large-scale production of human mesenchymal stem cells for clinical applications. Special Issue: Stem Cells and Regenerative Medicine. 2012;59(2):106–20.

CAS  Google Scholar 

Jung S, et al. Quality manufacturing of mesenchymal stem/stromal cells using scalable and controllable bioreactor platforms, in Bioreactors for Stem Cell Expansion and Differentiation. Boca Raton. 2018.

Shahdadfar A, et al. In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability. Stem cells (Dayton, Ohio). 2005;23(9):1357–66.

CAS  Google Scholar 

Wang Y, et al. Safety of mesenchymal stem cells for clinical application. Stem cells international. 2012;2012:652034–44.

PubMed  PubMed Central  Google Scholar 

Croughan MGD, Fang D, Lee B. Novel single-use bioreactors for scale-up of anchorage-dependent cell manufacturing for cell therapies. Stem Cell Manuf. 2016;105–139.

Lee B, et al. New Scalable Manufacturing Platform for Shear-Sensitive Cell Therapy Products. Cytotherapy (Oxford, England). 2016;18(6):S140–S140.

Google Scholar 

Sousa MF, et al. Production of oncolytic adenovirus and human mesenchymal stem cells in a single-use, Vertical-Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier-based cell culture processes. Biotechnol Prog. 2015;31(6):1600–12.

CAS  PubMed  Google Scholar 

Kirian RD, et al. Scaling a xeno-free fed-batch microcarrier suspension bioreactor system from development to production scale for manufacturing XF hMSCs. Cytotherapy. 2019;21(5).

Li A, et al. Advances in automated cell washing and concentration. Cytotherapy (Oxford, England), 2021.

Pattasseril J, Varadaraju H, Lock L, Rowley JA. Downstream technology landscape for large-scale therapeutic cell processing. Bioprocess Int. 2013;11(3):38–47.

Pandey PR, et al. End-to-end platform for human pluripotent stem cell manufacturing. Int J Mol Sci. 2019;21(1):89.

PubMed Central  Google Scholar 

Rozembersky JJ, et al. A novel scaleable acoustic cell processing platform for cell concentration and washing. Cytotherapy (Oxford, England). 2017;19(5):e17–e17.

Google Scholar 

Dominici M, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy (Oxford, England). 2006;8(4):315–317.

Wiese DM, Braid LR. Transcriptome profiles acquired during cell expansion and licensing validate mesenchymal stromal cell lineage genes. Stem Cell Res Ther. 2020;11(1):1–357.

Google Scholar 

Mirotsou M, et al. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A. 2007;104(5):1643–8.

CAS  PubMed  PubMed Central  Google Scholar 

Zhang M, et al. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. Faseb J. 2007;21(12):3197–207.

CAS  PubMed  Google Scholar 

Tang YL, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg. 2005;80(1):229–36; discussion 236–7.

Sadat S