The Rule of Science

CellR4 2013; 1 (2): e385



The use of MSCs for therapeutic purposes must be carefully considered. The scientific logic for their clinical use has recently been challenged, suggesting that the “Rule of Science” has been violated. A brief response is provided.

Paolo Bianco’s recent statements try to discredit the entire translational efforts using Mesenchymal Stem Cells (MSCs) without making any distinction within the over 350 clinical trials that currently use MSCs world-wide. Trying to discredit scientists and organizations with different opinions, because they do not fit with one’s myopic, narrow-minded and fundamentally misleading argument has recently raised serious concerns 1 , 2 , 3. It is unfortunate to witness a pattern of out of context, selected and distorted quotes (Demystifying Mesenchymal Stem Cells, Paolo Bianco, Lecture at the 12th International Congress of The Cell Transplant Society, Milan, Italy, July 11, 2013; While the reasons for this attitude are not apparent, they could be misinterpreted, perhaps, as a troubled attempt to gain fame by publishing inflammatory and polarizing perspectives 4 , rather than contributing to further the progress of science and clinical therapeutics.

It should be clear that we are the first to condemn the use of Mesenchymal Stem Cells (MSCs) when scientific methods are not adopted, that we consider patients’ safety central to all cell therapy translational efforts and that expanded clinical trials should not be considered before safety is established in pilot (Phase I, Phase I/II) clinical trials. Nevertheless, pilot clinical trials should not necessarily require previous proof of efficacy in the selected clinical application, especially for pathologic conditions for which a valid therapeutic alternative does not exist. In addition, we believe that historical medical outcomes should be strongly considered as opposed to placebo controls, again to protect patient’s safety (i.e., open label safety studies are useful when historical outcomes are known).

Before proven clinical benefits are established, well-designed clinical trials should be considered only in the presence of approval from an appropriate Institutional Review Board/Ethics Committee, with an adequate informed consent process in place and only when outcomes, possible side effects and serious adverse events are rigorously reported, monitored and reviewed by appropriate Data Safety Monitoring Boards (DSMBs), with defined stopping rules already included in the clinical protocols at their inception.


The Rules of Science requires that ALL of the facts be explained. The FACTS are:

Fact: MSCs can be isolated from a huge range of tissues and markers for their purification have been summarily published 5 , 6 , 7 , 8 , 9 , 10 , 11.

Explanation: MSCs are derived from perivascular cells, pericytes, and function at various sites of tissue injury 12 , 13 , 14.


Fact: Allogeneic or xenogeneic MSCs added systemically can CURE graft-vs-host disease, MS (EAE model), stroke, acute myocardial infarct, asthma (both acute and chronic lung inflammation), inflammatory bowel disease, kidney and liver fibrosis, urinary incontinence, sepsis, and on and on 15 , 16 , 17 , 18 , 19.

Explanation: MSCs stimulate powerful immunomodulatory and trophic effects 20.


Fact: MSCs are heterogeneous; only a very small fraction of these MSCs can be cloned.

Explanation: Life does not exist as a clone so if a heterogeneous mixture of cells works therapeutically, this is wonderful. Which cells do what in these therapeutic situations is what scientists are supposed to work on.


Fact: MSCs from a very limited number of tissues have been cloned and shown to possess “stem cell” properties.

Explanation: The name Mesenchymal Stem Cells does not explain their immunomodulatory or trophic effects and, therefore, Arnold Caplan who first proposed the MSC nomenclature has recently further proposed to call them “Medicinal Signaling Cells” to preserve the MSC acronym and correctly explain their function as immunomodulatory and trophic cells 21 , 22.


Fact: Freidenstein and Owen were among the first to describe the marrow MSC as a multipotent progenitor 23.

Explanation: There is a rich literature predating Caplan’s proposal of the Mesengenic Process. However, Caplan proposed a comprehensive hypothesis (he still calls it an hypothesis) in which adult MSCs could be induced to differentiate into a variety of mesodermal phenotypes 24. Caplan never suggested that these MSCs could differentiate into nerve, cardiac myocytes or other non-mesodermal phenotypes.


Fact: MSCs cannot differentiate into nerve or heart cells.

Explanation: Because MSCs are medicinal they can have profound therapeutic effects on stroke or AMI without differentiating into nerve or cardiac myocytes.


Fact: MSCs can have a profoundly positive effect on organ transplantation 25.

Explanation: MSCs modulate the immune-rejection chemistry and assist in the host-mediated repair of damaged vasculature and parenchymal tissue 26.


Fact: MSCs produce powerful antibiotic proteins when exposed to a range of different bacteria 27 , 28.

Explanation: Defensens have long been described and it is clear that they can be upregulated when bacteria are exposed to MSCs; thus, MSCs may, indeed, be a useful treatment for sepsis.


Fact: Arnold Caplan started Osiris Therapeutics and proudly publically discloses this at every public lecture.

Explanation: Caplan sued Osiris in 1997 in US Federal Court for breach of contract and has not had a formal relationship with Osiris since this time. Moreover, he owns no stock in Osiris and, thus, has nothing to gain from their successes except that many of their clinical observations support the concept that MSCs are medicinals. The data from Mesoblast, Cytori, Athersys, and other corporations likewise support the use of MSCs in various clinical contexts.



The simple Rule of Science is that with the accumulation of data, the hypotheses are proven or disproven and science progresses. Moreover, since most of biological science is tied to medical advancement and governmental (financial) support for such medical advancement, we scientist are ethically and morally obliged to extend our science into the medical arts where applicable. The use of MSCs in over 350 clinical trials listed on is exactly this extension. Paolo Bianco is still stuck in the 1980’s and 90’s and wants the Stem Cells to be his platform to deny us the due process of proving their therapeutic worth. Evidence Based Medicine is what we are doing and we are doing it on FIRM, PUBLISHED SCIENTIFICALLY SOUND DATA.

MSCs are, indeed, Drug Stores because they are naturally medicinals 29. Patients in need of these therapies should not be denied access because Dr. Bianco still wants MSCs to only make bone.


  1. Ricordi C. Towards a constructive debate and collaborative efforts to resolve current challenges in the delivery of novel cell based therapeutic strategies. CellR4 2013; 1(1): 2-7.  (back)
  2. Burt RK, Anversa P, Ricordi C. Moving towards a detente in the stem cell debate. CellR4 2013; 1(1): 1-1.  (back)
  3. Losordo DW, Zeiher AM. Angels and Demons: Part II. Circ Res 2013; 113: 20-21.  (back)
  4. Bianco P. Don’t market stem-cell products ahead of proof. Nature 2013; 499(7458): 255.  (back)
  5. Brighton CT, Lorich DG, Kupcha R, et al. The pericyte as a possible osteoblast progenitor-cell. Clin Orthop Relat Res 1992; (275): 287-299.  (back)
  6. Caplan AI. Biomaterials and Bone Repair. Biomaterials 1988; 87: 15-24.  (back)
  7. Krampera M, Marconi S, Pasini A, et al. Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus. Bone 2007; 40: 382-390.  (back)
  8. Bieback K, Schallmoser K, Klutera H, Strunk D. Clinical protocols for the isolation and expansion of mesenchymal stromal cells. Transfus Med Hemother 2008; 35: 286-294.  (back)
  9. Nakahara H, Goldberg VM, Caplan AI. Culture-expanded human periosteal-derived cells exhibit osteochondral potential in vivo. J Orthop Res 1991; 9: 465-476.  (back)
  10. Salingcarnboriboon R, Yoshitake H, Tsuji K, et al. Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Exp Cell Res 2003; 287: 289-300.  (back)
  11. March KL, Johnstone BH. Cellular approaches to tissue repair in cardiovascular disease: the more we know, the more there is to learn. Am J Physiol Heart Circ Physiol 2004; 287: H458-H463.  (back)
  12. Crisan M, Yap S, Casteiolla L, et al. A perivascular origin for mesenchymal stem cells in multiple human oragans. Cell Stem Cell 2008; 3: 301-313.  (back)
  13. da Silva Meirelles L, Caplan AI, Nardi NB. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2008; 26: 2287-2299.  (back)
  14. Penn MS, Khalil MK. Exploitation of stem cell homing for gene delivery. Expert Opin Biol Ther 2008; 8: 17-23.  (back)
  15. Black LL, Gaynor J, Gahring D, et al. Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial. Vet The 2007; 8: 272-284.  (back)
  16. Bonfield TL, Nolan MT (Koloze), Lennon D, et al. Defining mesenchymal stem cell efficacy in vivo. J Inflamm (Lond) 2010a; 7: 51.  (back)
  17. Bonfield TL, Nolan MT (Koloze), Lennon D, et al. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol 2010b; 299(6): L760-70.  (back)
  18. Garcia-Olmo D, Garcia-Arranz M, Herreros D, et al. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005; 48: 1416-1423.  (back)
  19. Penn MS, Zhang M, Deglurker I, Topol EJ. Role of stem cells homing in myocardial regeneration. Int J Cardiol 2004; 95: S23-S25.  (back)
  20. Caplan AI, Correa D. PDGF in bone formation and regeneration: New insights into a novel mechanism involving MSCs. J Orthop Res 2011; 29(12): 1795-1803.  (back)
  21. Caplan AI. Cell delivery and tissue regeneration. J Contr Release 1989; 11: 157-165.  (back)
  22. Caplan AI. What’s in a name? Tiss Eng Part A 2010; 16(8): 2415-2417.  (back)
  23. Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 1988; 136: 42-60.  (back)
  24. Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9: 641-650.  (back)
  25. Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, Sun X, Chen J, Yang S, Cai J, Gao X, Pileggi A, Ricordi C. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307(11): 1169-1177.  (back)
  26. Penn MS, Zhang M, Deglurker I, Topol EJ. Role of stem cells homing in myocardial regeneration. Int J Cardiol 2004; 95: S23-S25.  (back)
  27. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010; 28: 2229-2238.  (back)
  28. McCormick TS, Weinberg A. Epithelial cell-derived antimicrobial peptides are multi-functional agents that bridge innate and adaptive immmunity. Periodontology 2000; 54: 195-206.  (back)
  29. AI Caplan, D Correa. The MSC: An injury drugstore. Cell Stem Cell 2011; 9(1): 11-15.  (back)

To cite this article

The Rule of Science

CellR4 2013; 1 (2): e385

Publication History

Published online: 30 Sep 2013