The History of Co-Transplantation of UC-MSC and CB-HSC into Human Patients
Recently, two exciting studies in China were published that highlight the co-transplantation of human umbilical cord mesenchymal stem cells (UC-MSC) and human umbilical cord blood hematopoietic stem cells (CB-HSC) into human patients. These papers provide some of the first human data to support a scientific hypothesis that was first suggested at the 7th International Cord Blood Society (ICBS) Congress in 2004 (1).
In the late 1990's and early 2000's my son, Kyle Cetrulo, and I founded and ran the ICBS, a pioneering educational foundation that held annual symposia about cord blood research. The 7th ICBS Congress was held at Tufts New England Medical Center in October 2004. As we were planning the 2004 ICBS Congress, Drs. Kathy Mitchell and Mark Weiss from Kansas State University published papers that identified Wharton's Jelly from the umbilical cord as a source of MSCs (2,3,4). Wanting to learn more, we invited them to give a presentation.
At the time, I was a Professor of OB/GYN at Tufts University School of Medicine. I became interested in mesenchymal stem cells (MSC) as a more powerful cell type for regenerative medicine applications, especially when compared to the hematopoietic stem cells found in umbilical cord blood (CB-HSC). HSC are great at forming other blood cells such as red blood cells, white blood cells and platelets; but are not the best cell for regenerative medicine therapies that look to form new neurons, muscle, bone, cartilage and other tissue types to treat non-blood based diseases.
Coincidently, in the fall of 2004, Dr. Hans Klingemann was hired as the new Director of Bone Marrow Transplantation at Tufts New England Medical Center in Boston, and I made sure that he also attended the 7th ICBS Congress. I had big plans to involve Dr. Klingemann in our research on Wharton's Jelly stem cells - soon after the ICBS meeting, I began to deliver consented donations of placentas, umbilical cords and cord blood collected during my OB/GYN shifts to Dr. Klingemann�s laboratory. As the tissue specimens began to pile up, they generated the response I was looking for, and we began to collaborate.
Dr. Klingemann, with his oncology background where researchers were already using bone marrow derived MSC to enhance HSC transplantation (5,6,7), postulated that MSC from the Wharton's Jelly could be co-transplanted with the cord blood HSC in order to enhance the engraftment of the cord blood unit. Dr. Robb Friedman, Monica Betancur, and Dr. Laurent Boissel, who were working in Dr. Klingemann's laboratory, decided to focus on this research hypothesis. The results of this study demonstrated that human UC-MSC can support human CB-HSC in a NOD/SCID mouse transplant model. These results were published in a paper titled "Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation" (8).
In 2008, together with Dr. Rouzbeh R. Taghizadeh, we formed AuxoCell Laboratories, Inc., the world's first company to focus exclusively on developing the clinical potential of stem cells from Wharton's Jelly (aka Cord Tissue). Our approach is to focus on native, primary MSC from the cord tissue rather than expanded MSC. We find that minimally manipulated native MSC from the cord tissue are even more potent than culture expanded cord tissue MSC, when compared in a NOD/SCID mouse transplant model (9,10).
Nevertheless, I was excited to see two papers with human data come out of China, where culture expanded human UC-MSC are being used for clinical trials. The first paper, published in Transplantation in 2012 (11), is a pilot study that compared five patients who were co-transplanted with culture expanded UC-MSC and CB-HSC versus nine patients who were transplanted with CB-HSC alone. Of great significance, the co-transplanted group had significantly faster recovery of their immune system, reaching engraftment in a similar time frame as a bone marrow transplant. This is very important because cord blood transplants usually take 10 days longer than bone marrow to engraft.
The second study was published in Cell Transplantation in 2013 (12). In this article, UC-MSC and CB-HSC were co-transplanted first in animals and then in humans. Twenty human patients with high-risk leukemia were randomized to a co-transplant group versus a CB-HSC transplant group. Again, there were no serious adverse events and the engraftment time was significantly shorter in the eight patients receiving the co-transplantation regimen.
These two studies both show that co-transplantation of ex vivo expanded banked UC-MSC together with CB-HSC are safe in human patients and have the exciting potential of speeding engraftment to the gold standard set by bone marrow transplants. Hopefully, this data further encourages more robust studies using the powerful combination of UC-MSC and CB-HSC. We look forward to the day when human co-transplantation studies are authorized by the FDA in the United States.
- Cetrulo, et al., Wharton's Jelly Stem Cells: Isolation, Extraction and Prelminary Characterization, Biology of Blood and Marrow Transplantation, Kluge Carden Jennings Publishing, Charlottesville, VA, US 11(11):938 (2005)
- Mitchell KE, Weiss ML, Mitchell BM, Martin P, Davis D, Morales L, Helwig B, Beerenstrauch M, Abou-Easa K, Hildreth T, Troyer D, Medicetty S. Matrix cells from Wharton's jelly form neurons and glia. Stem Cells. 2003;21(1):50-60. Erratum in: Stem Cells. 2003;21(2):247. PubMed PMID: 12529551.
- Weiss ML, Mitchell KE, Hix JE, Medicetty S, El-Zarkouny SZ, Grieger D, Troyer DL. Transplantation of porcine umbilical cord matrix cells into the rat brain. Exp Neurol. 2003 Aug;182(2):288-99. PubMed PMID: 12895440.
- Medicetty S, Bledsoe AR, Fahrenholtz CB, Troyer D, Weiss ML. Transplantation of pig stem cells into rat brain: proliferation during the first 8 weeks. Exp Neurol. 2004 Nov;190(1):32-41. PubMed PMID: 15473978.
- Noort WA, Kruisselbrink AB, in't Anker PS, Kruger M, van Bezooijen RL, de Paus RA, Heemskerk MH, Löwik CW, Falkenburg JH, Willemze R, Fibbe WE. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol. 2002 Aug;30(8):870-8. PubMed PMID: 12160838.
- Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells. 2004;22(7):1330-7. PubMed PMID: 15579650.
- Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005 May;11(5):389-98. PubMed PMID: 15846293.
- Friedman R, Betancur M, Boissel L, Tuncer H, Cetrulo C, Klingemann H. Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation. Biol Blood Marrow Transplant. 2007 Dec;13(12):1477-86. PubMed PMID: 18022578.
- Taghizadeh RR, Cetrulo KJ, Cetrulo CL. Wharton's Jelly stem cells: future clinical applications. Placenta. 2011 Oct;32 Suppl 4:S311-5. doi: 10.1016/j.placenta.2011.06.010. Epub 2011 Jul 6. Review. PubMed PMID: 21733573.
- Taghizadeh, R.R., Perinatal Mesenchymal Stem Cell Banking for Umbilical Cord Blood Transplantations and Regenerative Medicine, Perinatal Stem Cells, Volume 2, Wiley-Blackwell Publishing, 53-69, 2013.
- Wu KH, Sheu JN, Wu HP, Tsai C, Sieber M, Peng CT, Chao YH. Cotransplantation of umbilical cord-derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: a pilot study. Transplantation. 2013 Mar 15;95(5):773-7. doi: 10.1097/TP.0b013e31827a93dd. PubMed PMID: 23274973.
- Wu KH, Tsai C, Wu HP, Sieber M, Peng CT, Chao YH. Human Application of Ex-Vivo Expanded Umbilical Cord-Derived Mesenchymal Stem Cells: Enhance Hematopoiesis after Cord Blood Transplantation. Cell Transplant. 2013 Feb 26. doi: 10.3727/096368913X663523. [Epub ahead of print] PubMed PMID: 23452720.