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  • 1. What treatment needs does regenerative medicine meet ?
  • 2. What is the origin of stem cells used for regenerative medicine ?
  • 3. What are the properties of and sources of MSCs
  • 4. What are the mechanisms of action of MSCs that stimulate a concerted repair of injured tissue ?
  • 5. Where are MSCs used in the clinic ?
  • 6. Why use umbilical cord derived cells ?
  • 7. Do MSCs of different origin have the same biological potential ?
  • 8. Why are umbilical cord cells becoming the cell of choice ?
  • 9. Veterinary medical and in particular equine clinical data are fewer and more difficult to interpret.

1. What treatment needs does regenerative medicine meet ?

The body has its own natural resources to regenerate injured tissue. However, these may be of limited capacity and in certain tissues be non-existent. (e.g. articular cartilages).
Often in the case of some acute injuries  (fractures) or chronic conditions (tendonitis) or certain degenerative diseases,  the body initiates an healing process  but calluses or scar tissue can form and prevent  full restoration of tissue function
Regenerative medicine augments naturally healing process to help create functional living tissue or to replace damaged tissues and organs.
Regeneration can be done in situ by stimulating damaged organs or in the laboratory.
Stem cell use is the main axis of regenerative medicine.

Indeed in 2011 alone, 7000 studies examining the use of MSCs were published. Pubmed (reference site)

2. What is the origin of stem cells used in regenerative medicine ?

Different cell types are included in the generic term “stem cells”.
Embryonic stem cells (ES cells) are the most primitive but their clinical use is controversial. Control in vivo is difficult and primitive cancers may arise (teratomas).

Induced pluri-potent stem cells (iPS) are differentiated cells which have been genetically reprogrammed into a more controllable undifferentiated state.

However, to date there is not enough data to asses their safety.

On the other hand-multi-potent mesenchymal stem cells (MSCs), have been proven to be safer. They can be isolated from several convenient sources and have the power to differentiate into many cell types including bone, cartilage, tendon, muscle or neuronal tissue

3. What are the properties and sources of MSCs?

The earliest, characterised stromal  stem cells were isolated from murine bone marrow and were originally described to have osteogenic potential  (A.J.Friedenstein Exp Hematol. 4: (1976) 267-274)

Since then they have been detected in almost all adult tissues such as vascularised bone marrow or adipose tissue in varying numbers. Recently, MSCs have been confirmed to be present in placental tissue and some reports suggest they may be also found in placental blood;(Kern S. Stem Cells 2006 24:1294-1301),

Neonatal CSM are systematically present in umbilical cord blood and in Wharton’s jelly, a connective tissue that surrounds and protects the blood vessels of the umbilical cord

The amniotic fluid, amniotic membranes and sack (bag of waters) also contain MSCs (Iacono, E. (2012) Reproduction 143;4:455-468)

MSCs are generally characterised by:

• Their ability to adhere to plastic.
• Expression of certain combinations of surface markers (e g. proteins with an extra-cellular component)
• The  power of differentiation in vitro, in defined culture media  into  three different cell lineages: chondrocytes (cartilage), osteoblasts (bone), or adipocytes (fat tissue)

4. What are the mechanisms of action of MSCs that stimulate a concerted repair of injured tissue?

• They differentiati in vivo and directly repair tissue (Pittenger MF. Science 284 (1999) 143-147).

This mechanism has been demonstrated in various animal models although, it’s impact is now considered minor because only a very small proportion of the injected cells are found in situ several months after injection.

• The primary repair process is now recognised to involve several paracrine mechanisms:

o Angiogenic.- MSCs secrete a growth factor, VEGF (Vascular Endothelium Growth Factor) which stimulates vascularisation (Müller I. (2008)  Leukemia (2008) 22: 2054-2061.
o Anti-apoptotic- MSCs prevent the death of the injured tissue resident cells o Anti-inflammatory (Lee, HR Cell Stem Cell 2009 5: 54-63; Ortiz LA, Proc Natl Acad Sci USA (2007) 104: 11002-11007;
o Anti-fibrotic (Ortiz LA, Proc Natl Acad Sci USA (2007) 104: 11002-11007
o Immuno-modulatory. MSCs interact with various cellular components involved in  acquired immunity, both,innate and humoral to limit the development of an aberrant immune response (Exp Hematol (2003) K. Leblanc 31: 890-896; Götherström C. Am J Obstet Gynecol 2004 190: 239-245. Such interaction is through cell contact or secretion of soluble factors (eg: IDO, LIF, HLA-G, PGE2, IL-6, NO, TGFb, IL-10) that induces an environment of immune tolerance.

o Stimulation of the recruitment of host stem cells to the site of injury.

5. Where are MSCs used in the clinic?

The first evidence of cells with a potential for healing dates back more than 140 years, Following intravenous injection cytochrome labelled cells were detected at  induced  injury sites,’ Julius F.Chonheim.. Conheim. Über Entzündung und Eiterung Arch. Path. Anat. Physiol. Klin . Med. 40: (1867) 1-79)

MSCs have been employed in numerous clinical situations but primarily for those where current treatments are inadequate (Examples are given below)..

Early studies, however either used un-processed or concentrated bone marrow or fat cells for injection. Injection of mixed populations sometimes led to undesirable side effects largely eliminated by using pure populations of MSCs

In 2011, 226 new human clinical trials were initiated using purified MSCs similar to those produced by Vetbiobank. ( MARROSTEM®,OMBISTEM®, OMBISTEM PLUS®)

A Cartilage Regeneration

– Regeneration of a meniscus in a goat model (Murphy JM. et al. Arthritis Rheum  (2003) 48: 3464-3474)
– Repair of cartilage in 41 patients (Wakitani SJ Tissue Eng. Regen. Med. (2010))
– Cartilage repair is as effective using autologous chondrocyte transplantation and much less invasive. Nejadnik H. Am J. Sports Med (2010) 38:1110-1116

B – Bone Regeneration

– Fracture with large defect. 3 patients (Quarto R. N.Engl. J.Med 2001) 344: 385-386.
– Fracture with risk of non-union. 60 patients (Hernigou P J. Bone Joint Surg Am (2005)  87: 1430 t- 1437.
– Treatment of Osteogenesis Imperfecta in 5 patients (Horwitz EM. Regenerative Cell Therapy. Flight 11 Springer. Berlin Heidelberg (2005) 69-80.
– Avascular osteonecrosis (Müller I. Leukemia 22 (2008) 2054-2061 Hernigou and P. J Bone Joint Surg Br 87 (2005) 896-902 and T.Yoshioka Int.Orthop (2011 )35: 823-829)

C- Regeneration of tendons.

The high levels of tendon injuries in race horses has impacted greatly on the number of clinical trials using stem cells; see:

– A. Crovace Ve.t Res. Comm. (2007) 3: (suppl. 1) 281-283.
– Guest DJ. Eq. J. Vet. (2008)  40: 178-181.
– Nixon AJ. Am. J. Vet. Res. (2008) 928-937.

However encouraging results can be improved upon since:

  • The products used are very heterogeneous as in the early studies
    Total bone marrow contains mature osteoblaststaht that could be responsible for the formation of mineralised zones after intra-tendonous or intracardiac injection  (SM Hashemi. Eur. Heart J. 29 (2008) 251-259)
  • The quality of samples taken is not monitored sufficiently
  • These samples do not provide a sufficient number of treat fractures fractures, the quality and speed of bone repair is correlated with wealth (CSM Hernigou P. J Bone Joint Surg Am 87 (2005) -1430 – 1437.

These studies provide the basis and need for amplification and purification of MSCs

VETBIOBANK supplies only highly purified and characterised populations of MSCs.

6. Why use umbilical cord blood cells ?

In 2011 alone 33 new clinical trials using MSCs derived from cord blood were registered (see:

The use of neonatal MSCs accelerates bone formation in a dog model of non-union fracture (Jang BJJJ. J Vet Sci 2008 9: 387-393)

  • Horse studies
    • Applications in the repair of cartilage (L. Fortier J Bone Joint Surg Am (2010) 92: 1927-1937
    • Tendonitis SFDT experimental (Crovace Vet Res Commun (2010) A.31: 281-283)
  • Concentrated fat “point of care” device
    • Experimental Tendinitis (Nixon 2007)
    • Osteoarthritis
      • Model fragment endochondral => no improvement Frisbie (2009)
  • Concentrated stem cell studies.
    • Fortier, LA, et al., bone marrow aspirate Concentrated full-thickness cartilage Improves repair Compared with micro-fracture in the equine model. J Bone Joint Surg Am (2010). 92:1927-37..
    • Yoshioka, T., et al. Concentrated autologous bone marrow aspirate transplantation treatment for corticosteroid-induced osteonecrosis of the femoral head in systemic lupus erythematosus. Int Orthop, (2011) 35: 823-9

7. Do MSCs of different origin have the same biological potential ?

Other sources of stem cells have been identified (synovial membrane and synovial fluid, tendons, peripheral blood) which may offer more potential to treat injuries that occur in their tissue of origin. Data for the moment is not available

8. Why are umbilical cord MSCs becoming the cell of choice ?

Bone marrow, obtained from an adult donor has been the norm in France since 1996, for haemopoietic stem cell transplants that reconstitute the chemo or radio ablated marrow of  patients with leukemia or lymphoma;

Transplants using cord blood donations have become more frequent.

This trend is due to several factors relating to the cellular and immunological immaturity of the cells:

  • An higher proliferative potential, cells entering senescence after several divisions (2004 Baxter MA Stem Cells 22: 675-682)
  • Their differentiation potential is maintained after culture and expansion, this is not the case for adult MSCs from bone marrow  see Stenderup K. Bone 33 (2003) 919-926 and Wagner W. Tissue Eng. B 16: 1981 – 1984
  • A lowered immunological reaction to the graft even in cases of incompatibility between  recipient and  donor.
  • Superior product warranties are available.
  • A more extensive quality control of the product is possible.
  • Simpler logistics – Umbilical cord blood can be collected easily immediately after birth with very little risk to mother and offspring.

9. Veterinary medicical and in particular equine clinical data are fewer and more difficult to interpret.

The use of MSCs is an advanced relatively expensive technique, and therefore restricted to animals with high economic value, such as race horses.The downside is that equine clinical studies do not have suitable controls and are often thus compared with epidemiological data.
In addition, MSCs, either, equine or canine are less easy to characterise because of the lack of commercial reagents specific to the species.
Finally, clinical treatment and adherence to a standardised protocols are difficult to control outside an hospital setting.

A comprehensive review on the use of stem cells in equine regenerative medicine is  however, available: Veterinary Clinics of North America Equine Practice 27:– Issue 2

Warning: Notice:

 Published autologous transplant clinical studies showing the efficacy of treatment need to be expanded tofurther define the level of effectiveness of the approach compared to standard treatment regimes

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