Mesenchymal or Maintenance Stem Cell & Understanding Their Role in Osteoarthritis of the Knee Joint: A Review Article



1 Department of Orthopaedics, Saudi German Hospital, Dubai, UAE

2 GEMS Modern Academy, Dubai UAE


Mesenchymal Stem Cell (MSC) therapy in osteoarthritis has been hailed as a promising treatment for osteoarthritis due
to their unlimited potential of healing and regeneration. Existing literature regarding their proper name, optimal sources,
mechanisms of action, dosage, and route of administration, efficacy, and safety is debatable. This index review article
has tried to connect these puzzling pieces of available information and brought clarity on some of these crucial issues.
The author believes that Maintenance Stem Cells (MSC) may be a more suitable term than mesenchymal stem cell or
medicinal signaling cells as their origin might not be limited to mesodermal tissue. Also, they have been shown capable
of self-renewal, differentiation, and maintaining a cascade of healing & possibly regeneration at the implanted site. Only
a small percentage of implanted MSC survive and rest undergo apoptosis after releasing growth factors, cytokines, and
extracellular vesicles. These surviving MSC become active due to conformational changes induced by anti-environment
stimuli and undergo limited self-renewal, proliferation, and differentiation, but only a few of them might incorporate into the
host tissues. These cells generate & maintain a momentum of series of regenerative activities to improve the function of
joint, stabilize or possibly enhance the cartilage quality. More randomized studies with long term follow-up are required to
bring clarity on their ideal source, expansion, culture technique, optimum dosage, and route of administration and longterm
safety issues.
Level of evidence: V


1. Caplan AI. Mesenchymal stem cells. Journal of
orthopaedic research. 1991; 9(5):641-50.
2. Beane OS, Darling EM. Isolation, characterization,
and differentiation of stem cells for cartilage
regeneration. Annals of biomedical engineering.
2012; 40(10):2079-97.
3. Horwitz EM, Le Blanc K, Dominici M, Mueller I,
Slaper-Cortenbach I, Marini FC, et al. Clarification of
the nomenclature for MSC: The International Society
for Cellular Therapy position statement. Cytotherapy.
2005; 7(5):393-5.
4. Dominici ML, Le Blanc K, Mueller I, Slaper-Cortenbach
I, Marini FC, Krause DS, et al. Minimal criteria for
defining multipotent mesenchymal stromal cells. The
International Society for Cellular Therapy position
statement. Cytotherapy. 2006; 8(4):315-7.
5. Caplan AI. Mesenchymal stem cells: time to change 
the name!. Stem cells translational medicine. 2017;
6. Shafiee A, Seyedjafari E, Soleimani M, Ahmadbeigi
N, Dinarvand P, Ghaemi N. A comparison between
osteogenic differentiation of human unrestricted
somatic stem cells and mesenchymal stem cells from
bone marrow and adipose tissue. Biotechnology
letters. 2011; 33(6):1257-64.
7. Wu W, Le AV, Mendez JJ, Chang J, Niklason LE,
Steinbacher DM. Osteogenic performance of
donor-matched human adipose and bone marrow
mesenchymal cells under dynamic culture. Tissue
Engineering Part A. 2015; 21(9-10):1621-32.
8. Xu L, Liu Y, Sun Y, Wang B, Xiong Y, Lin W, et al. Tissue
source determines the differentiation potentials of
mesenchymal stem cells: a comparative study of
human mesenchymal stem cells from bone marrow 
and adipose tissue. Stem cell research & therapy.
2017; 8(1):1-1.
9. Tremolada C, Beltrami G, Magri A, Bianchi F, Ventura
C, Di Vito C, et al. Adipose mesenchymal stem cells and
“regenerative adipose tissue graft” (Lipogems™) for
musculoskeletal regeneration. Eur J Musculoskelet
Dis. 2014; 3(2):57-67.
10. Bianchi F, Maioli M, Leonardi E, Olivi E, Pasquinelli
G, Valente S, et al. A new nonenzymatic method and
device to obtain a fat tissue derivative highly enriched
in pericyte-like elements by mild mechanical forces
from human lipoaspirates. Cell transplantation.
2013; 22(11):2063-77.
11. Rath SN, Nooeaid P, Arkudas A, Beier JP, Strobel LA,
Brandl A,et al. Adipose‐and bone marrow‐derived
mesenchymal stem cells display different osteogenic
differentiation patterns in 3D bioactive glassbased
scaffolds. Journal of tissue engineering and
regenerative medicine. 2016; 10(10):E497-509.
12. Heo JS, Choi Y, Kim HS, Kim HO. Comparison of
molecular profiles of human mesenchymal stem cells
derived from bone marrow, umbilical cord blood,
placenta and adipose tissue. International journal of
molecular medicine. 2016; 37(1):115-25.
13. Beane OS, Fonseca VC, Cooper LL, Koren G, Darling
EM. Impact of aging on the regenerative properties
of bone marrow-, muscle-, and adipose-derived
mesenchymal stem/stromal cells. PloS one. 2014;
14. Choudhery MS, Badowski M, Muise A, Pierce J, Harris
DT. Donor age negatively impacts adipose tissuederived
mesenchymal stem cell expansion and
differentiation. Journal of translational medicine.
2014; 12(1):8.
15. Phinney DG, Kopen G, Righter W, Webster S, Tremain
N, Prockop DJ. Donor variation in the growth
properties and osteogenic potential of human marrow
stromal cells. Journal of cellular biochemistry. 1999;
16. Siddappa R, Licht R, van Blitterswijk C, de Boer J.
Donor variation and loss of multipotency during in
vitro expansion of human mesenchymal stem cells
for bone tissue engineering. Journal of orthopaedic
research. 2007; 25(8):1029-41.
17. Jurgens WJ, van Dijk A, Doulabi BZ, Niessen FB, Ritt
MJ, van Milligen FJ, et al. Freshly isolated stromal
cells from the infrapatellar fat pad are suitable for a
one-step surgical procedure to regenerate cartilage
tissue. Cytotherapy. 2009; 11(8):1052-64.
18. Koh YG, Choi YJ. Infrapatellar fat pad-derived
mesenchymal stem cell therapy for knee
osteoarthritis. The Knee. 2012; 19(6):902-7.
19. Tangchitphisut P, Srikaew N, Numhom S,
Tangprasittipap A, Woratanarat P, Wongsak S, et
al. Infrapatellar fat pad: an alternative source of
adipose-derived mesenchymal stem cells. Arthritis.
2016; 2016.
20. Hindle P, Khan N, Biant L, Péault B. The infrapatellar
fat pad as a source of perivascular stem cells with
increased chondrogenic potential for regenerative
medicine. Stem Cells Translational Medicine. 2017;
21. Shirasawa S, Sekiya I, Sakaguchi Y, Yagishita K, Ichinose
S, Muneta T. In vitro chondrogenesis of human
synovium‐derived mesenchymal stem cells: Optimal
condition and comparison with bone marrowderived
cells. Journal of cellular biochemistry. 2006;
22. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T.
Comparison of human stem cells derived from various
mesenchymal tissues: superiority of synovium as a
cell source. Arthritis & Rheumatism: Official Journal
of the American College of Rheumatology. 2005;
23. Bartolucci J, Verdugo FJ, González PL, Larrea RE,
Abarzua E, Goset C, et al. Safety and efficacy of the
intravenous infusion of umbilical cord mesenchymal
stem cells in patients with heart failure: a phase
1/2 randomized controlled trial (RIMECARD
trial [randomized clinical trial of intravenous
infusion umbilical cord mesenchymal stem cells on
cardiopathy]). Circulation research. 2017; 121(10):
24. González PL, Carvajal C, Cuenca J, Alcayaga-Miranda F,
Figueroa FE, Bartolucci J, et al. Chorion mesenchymal
stem cells show superior differentiation,
immunosuppressive, and angiogenic potentials in
comparison with haploidentical maternal placental
cells. Stem cells translational medicine. 2015;
25. Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey
PG, Shi S. SHED: stem cells from human exfoliated
deciduous teeth. Proceedings of the National
Academy of Sciences. 2003; 100(10):5807-12.
26. Shi S, Bartold PM, Miura M, Seo BM, Robey PG,
Gronthos S. The efficacy of mesenchymal stem cells to
regenerate and repair dental structures. Orthodontics
& craniofacial research. 2005; 8(3):191-9.
27. Gupta PK, Das AK, Chullikana A, Majumdar AS.
Mesenchymal stem cells for cartilage repair in
osteoarthritis. Stem cell research & therapy. 2012;
28. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell
therapy in a caprine model of osteoarthritis. Arthritis
& Rheumatism: Official Journal of the American
College of Rheumatology. 2003; 48(12):3464-74.
29. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-
Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic
and antiapoptotic factors by human adipose stromal
cells. Circulation. 2004; 109(10):1292-8.
30. Block GJ, Ohkouchi S, Fung F, Frenkel J, Gregory C,
Pochampally R, et al. Multipotent stromal cells are
activated to reduce apoptosis in part by upregulation
and secretion of stanniocalcin‐1. Stem cells. 2009;
31. Caplan AI. Why are MSCs therapeutic? New data:
new insight. The Journal of Pathology: A Journal of
the Pathological Society of Great Britain and Ireland.
2009; 217(2):318-24.
32. Freitag J, Bates D, Boyd R, Shah K, Barnard A,
Huguenin L, et al. Mesenchymal stem cell therapy in
the treatment of osteoarthritis: reparative pathways,
safety and efficacy–a review. BMC musculoskeletal
disorders. 2016; 17(1):230.
33. Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A,
Volarevic V. Mesenchymal stem cell-based therapy
of osteoarthritis: Current knowledge and future
perspectives. Biomedicine & pharmacotherapy.
2019; 109:2318-26.
34. Rochefort GY, Delorme B, Lopez A, Hérault O, Bonnet
P, Charbord P, et al. Multipotential mesenchymal stem
cells are mobilized into peripheral blood by hypoxia.
Stem cells. 2006; 24(10):2202-8.
35. Toupet K, Maumus M, Luz-Crawford P, Lombardo
E, Lopez-Belmonte J, van Lent P, et al. Survival and
biodistribution of xenogenic adipose mesenchymal
stem cells is not affected by the degree of inflammation
in arthritis. PLoS One. 2015; 10(1):e0114962.
36. Toupet K, Maumus M, Peyrafitte JA, Bourin P, van
Lent PL, Ferreira R, et al. Long‐term detection of
human adipose‐derived mesenchymal stem cells
after intraarticular injection in SCID mice. Arthritis &
Rheumatism. 2013; 65(7):1786-94.
37. Karp JM, Teo GS. Mesenchymal stem cell homing: the
devil is in the details. Cell stem cell. 2009; 4(3):206-
38. Wynn RF, Hart CA, Corradi-Perini C, O’Neill L, Evans
CA, Wraith J, et al. A small proportion of mesenchymal
stem cells strongly expresses functionally active
CXCR4 receptor capable of promoting migration to
bone marrow. Blood. 2004; 104(9):2643-5.
39. Caplan AI. Why are MSCs therapeutic? New data:
new insight. The Journal of Pathology: A Journal of
the Pathological Society of Great Britain and Ireland.
2009; 217(2):318-24.
40. Goldring MB. Osteoarthritis and cartilage: the role
of cytokines. Current rheumatology reports. 2000;
41. Loeser RF. Aging and osteoarthritis: the role of
chondrocyte senescence and aging changes in the
cartilage matrix. Osteoarthritis and cartilage. 2009;
42. Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow
LL, Yocum SA, Rosner PJ, et al. Cloning, expression,
and type II collagenolytic activity of matrix
metalloproteinase-13 from human osteoarthritic
cartilage. The Journal of clinical investigation. 1996;
43. Warstat K, Meckbach D, Weis-Klemm M, Hack A,
Klein G, de Zwart P, et al. TGF-β enhances the integrin
α2β1-mediated attachment of mesenchymal stem
cells to type I collagen. Stem cells and development.
2010; 19(5):645-56.
44. Hopper N, Wardale J, Brooks R, Power J, Rushton
N, Henson F. Peripheral blood mononuclear cells
enhance cartilage repair in in vivo osteochondral
defect model. PLoS One. 2015; 10(8):e0133937.
45. Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K,
Jee CS, et al. Articular cartilage regeneration with
autologous peripheral blood progenitor cells and
hyaluronic acid after arthroscopic subchondral
drilling: a report of 5 cases with histology.
Arthroscopy: The Journal of Arthroscopic & Related 
Surgery. 2011; 27(4):493-506.
46. Melief SM, Geutskens SB, Fibbe WE, Roelofs H.
Multipotent stromal cells skew monocytes towards
an anti-inflammatory interleukin-10-producing
phenotype by production of interleukin-6.
Haematologica. 2013; 98(6):888-95.
47. François M, Romieu-Mourez R, Li M, Galipeau J.
Human MSC suppression correlates with cytokine
induction of indoleamine 2, 3-dioxygenase and
bystander M2 macrophage differentiation. Molecular
Therapy. 2012; 20(1):187-95.
48. Chen W, Frank ME, Jin W, Wahl SM. TGF-β released by
apoptotic T cells contributes to an immunosuppressive
milieu. Immunity. 2001; 14(6):715-25.
49. Korns DR, Frasch SC, Fernandez-Boyanapalli R,
Henson PM, Bratton DL. Modulation of macrophage
efferocytosis in inflammation. Frontiers in
immunology. 2011; 2:57.
50. McDonald PP, Fadok VA, Bratton D, Henson PM.
Transcriptional and translational regulation of
inflammatory mediator production by endogenous
TGF-β in macrophages that have ingested
apoptotic cells. The Journal of Immunology. 1999;
51. Aggarwal S, Pittenger MF. Human mesenchymal stem
cells modulate allogeneic immune cell responses.
Blood. 2005; 105(4):1815-22.
52. Corcione A, Benvenuto F, Ferretti E, Giunti D,
Cappiello V, Cazzanti F, et al. Human mesenchymal
stem cells modulate B-cell functions. Blood. 2006;
53. Tabera S, Pérez-Simón JA, Dí􀆴ez-Campelo M, Sánchez-
Abarca LI, Blanco B, López A, et al. The effect of
mesenchymal stem cells on the viability, proliferation
and differentiation of B-lymphocytes. haematologica.
2008; 93(9):1301-9.
54. Caplan AI. Adult mesenchymal stem cells for tissue
engineering versus regenerative medicine. Journal of
cellular physiology. 2007; 213(2):341-7.
55. Zwolanek D, Satué M, Proell V, Godoy JR, Odörfer
KI, Flicker M, et al. Tracking mesenchymal
stem cell contributions to regeneration in an
immunocompetent cartilage regeneration model. JCI
insight. 2017; 2(20).
56. de Windt TS, Vonk LA, Slaper‐Cortenbach IC, Nizak R,
van Rijen MH, Saris DB. Allogeneic MSCs and recycled
autologous chondrons mixed in an one‐stage cartilage
cell transplantion: A first‐in‐man trial in 35 patients.
Stem Cells. 2017; 35(8):1984-93.
57. Bruno S, Tapparo M, Collino F, Chiabotto G, Deregibus
MC, Soares Lindoso R, et al. Renal regenerative
potential of different extracellular vesicle populations
derived from bone marrow mesenchymal stromal
cells. Tissue Engineering Part A. 2017; 23(21-
58. Lai RC, Yeo RW, Tan SS, Zhang B, Yin Y, Sze NS, et al.
Mesenchymal stem cell exosomes: the future MSCbased
therapy?. InMesenchymal stem cell therapy
2013 (pp. 39-61). Humana Press, Totowa, NJ.
59. Saas P, Bonnefoy F, Toussirot E, Perruche S. Harnessing
apoptotic cell clearance to treat autoimmune 
arthritis. Frontiers in immunology. 2017; 8:1191.
60. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott
JY, Henson PM. Macrophages that have ingested
apoptotic cells in vitro inhibit proinflammatory
cytokine production through autocrine/paracrine
mechanisms involving TGF-beta, PGE2, and PAF. The
Journal of clinical investigation. 1998; 101(4):890-8.
61. Griffith TS, Kazama H, VanOosten RL, Earle JK,
Herndon JM, Green DR, et al. Apoptotic cells induce
tolerance by generating helpless CD8+ T cells that
produce TRAIL. The Journal of Immunology. 2007;
62. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet
M, et al. Treatment of knee osteoarthritis with
autologous mesenchymal stem cells: a pilot study.
Transplantation. 2013; 95(12):1535-41.
63. Emadedin M, Labibzadeh N, Liastani MG, Karimi A,
Jaroughi N, Bolurieh T, et al. Intra-articular implantation
of autologous bone marrow–derived mesenchymal
stromal cells to treat knee osteoarthritis: a
randomized, triple-blind, placebo-controlled phase
1/2 clinical trial. Cytotherapy. 2018; 20(10):1238-46.
64. Koh YG, Kwon OR, Kim YS, Choi YJ. Comparative
outcomes of open-wedge high tibial osteotomy with
platelet-rich plasma alone or in combination with
mesenchymal stem cell treatment: a prospective
study. Arthroscopy: The Journal of Arthroscopic &
Related Surgery. 2014; 30(11):1453-60.
65. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui
JH. Injectable cultured bone marrow–derived
mesenchymal stem cells in varus knees with
cartilage defects undergoing high tibial osteotomy:
a prospective, randomized controlled clinical
trial with 2 Years’ follow-up. Arthroscopy: The
Journal of Arthroscopic & Related Surgery. 2013;
66. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C,
Barry F, et al. Adipose mesenchymal stromal cellbased
therapy for severe osteoarthritis of the knee: A
phase i dose‐escalation trial. Stem cells translational
medicine. 2016; 5(7):847-56.
67. Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH. Adiposederived
mesenchymal stem cells with microfracture
versus microfracture alone: 2-year follow-up of a
prospective randomized trial. Arthroscopy: The
Journal of Arthroscopic & Related Surgery. 2016;
68. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC,
et al. Intra‐articular injection of mesenchymal stem
cells for the treatment of osteoarthritis of the knee:
a proof‐of‐concept clinical trial. Stem cells. 2014;
69. Pak J, Chang JJ, Lee JH, Lee SH. Safety reporting on
implantation of autologous adipose tissue-derived
stem cells with platelet-rich plasma into human
articular joints. BMC musculoskeletal disorders.
2013; 14(1):337.
70. Bansal H, Comella K, Leon J, Verma P, Agrawal D, Koka
P, et al. Intra-articular injection in the knee of adipose
derived stromal cells (stromal vascular fraction) and
platelet rich plasma for osteoarthritis. Journal of 
translational medicine. 2017; 15(1):141.
71. Gupta PK, Chullikana A, Rengasamy M, Shetty
N, Pandey V, Agarwal V, et al. Efficacy and safety
of adult human bone marrow-derived, cultured,
pooled, allogeneic mesenchymal stromal cells
(Stempeucel®): preclinical and clinical trial in
osteoarthritis of the knee joint. Arthritis research &
therapy. 2016; 18(1):301.
72. Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC,
O’Connor MI. A prospective, single-blind, placebocontrolled
trial of bone marrow aspirate concentrate
for knee osteoarthritis. The American journal of
sports medicine. 2017; 45(1):82-90.
73. Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M,
Koyama T, et al. Safety of autologous bone marrowderived
mesenchymal stem cell transplantation for
cartilage repair in 41 patients with 45 joints followed
for up to 11 years and 5 months. Journal of Tissue
Engineering and Regenerative Medicine. 2011;
74. Vangsness Jr CT, Jack Farr II, Boyd J, Dellaero DT, Mills
CR, LeRoux-Williams M. Adult human mesenchymal
stem cells delivered via intra-articular injection to
the knee following partial medial meniscectomy: a
randomized, double-blind, controlled study. JBJS.
2014; 96(2):90-8.
75. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó
F, Nuñez-Córdoba JM, Sánchez-Echenique C, et al.
Intra-articular injection of two different doses of
autologous bone marrow mesenchymal stem cells
versus hyaluronic acid in the treatment of knee
osteoarthritis: multicenter randomized controlled
clinical trial (phase I/II). Journal of translational
medicine. 2016; 14(1):246.
76. Song Y, Du H, Dai C, Zhang L, Li S, Hunter DJ, et al.
Human adipose-derived mesenchymal stem cells for
osteoarthritis: a pilot study with long-term followup
and repeated injections. Regenerative medicine.
2018; 13(3):295-307.
77. Spasovski D, Spasovski V, Baščarević Z, Stojiljković M,
Vreća M, Anđelković M, et al. Intra‐articular injection
of autologous adipose‐derived mesenchymal stem
cells in the treatment of knee osteoarthritis. The
journal of gene medicine. 2018; 20(1):e3002.
78. Freitag J, Bates D, Wickham J, Shah K, Huguenin L,
Tenen A, et al. Adipose-derived mesenchymal stem
cell therapy in the treatment of knee osteoarthritis: a
randomized controlled trial. Regenerative medicine.
2019; 14(3):213-30.
79. Peeters CM, Leijs MJ, Reijman M, van Osch GJ,
Bos PK. Safety of intra-articular cell-therapy with
culture-expanded stem cells in humans: a systematic
literature review. Osteoarthritis and Cartilage. 2013;
80. Centeno CJ, Al-Sayegh H, Freeman MD, Smith J,
Murrell WD, Bubnov R. A multi-center analysis of
adverse events among two thousand, three hundred
and seventy two adult patients undergoing adult
autologous stem cell therapy for orthopaedic
conditions. International orthopaedics. 2016; 40(8):
81. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C,
Barry F, et al. Adipose mesenchymal stromal cellbased
therapy for severe osteoarthritis of the knee: A
phase i dose‐escalation trial. Stem cells translational
medicine. 2016; 5(7):847-56.
82. Schiavi J, Keller L, Morand DN, Isla ND, Huck O,
Lutz JC, et al. Active implant combining human
stem cell microtissues and growth factors for boneregenerative
nanomedicine. Nanomedicine. 2015;