MSCs for Tissue Engineered Tracheas and Enhanced Fracture Healing

For all my readers who have ever broken a bone, this one’s for you.

Setting a broken bone properly can lead to the healing of a broken bone, but large fractures that generate gaps in bones are very hard to heal. Stem cell therapy in combination with small protein molecules called cytokines has the potential to improve bone repair, since cytokines summon resident stem cells to migrate and home to the injured site. Having said that, the engraftment, participation and recruitment of other cells within the regenerating tissue are equally important.

To stimulate stem cell-mediated healing, University College London scientists over-expressed the SDF-1 protein in mesenchymal stem cells. Since SDF-1 is a stem cell-recruitment protein, it seems reasonable to suspect that these engineered cells would effectively increase the migration of native cells to the site of fracture and enhance bone repair.

Once they made SDF-1-expressing mesenchymal stem cells, Chih-Yuan Ho and colleagues showed that these cells increased the migration of non-transfected cells in a cell culture system.

Once these SDF-1-expressing mesenchymal stem cells were implanted into rats with large bone defects, bone marrow mesenchymal stem cells that over-expressed SDF-1 showed significantly more new bone formation within the gap and less bone mineral loss at the areas next to the defect site during the early bone healing stage.

Thus, SDF-1 plays an important role in accelerating fracture repair and contributing to bone repair, at least in this rat model. SDF-1 does this by recruiting more host stem cells to the defect site and encouraging their differentiation into bone cells, which go on to produce good-quality bone.  This paper appeared the the journal Tissue Engineering, Part A.

In a second paper that appeared in the Annals of Biomedical Engineering, mesenchymal stem cells were used to tissue engineer tracheae. In this case a biocompatible scaffold was seeded various with various cells and this strategy could be a solution for tracheal reconstruction.

Yoo Seob Shin and colleagues seeded mesenchymal stem cells (MSCs) on a scaffold made from pig cartilage powder (PCP). The PCP was made with minced and decellularized pig joint cartilage and was molded into a 5 × 12 mm (height × diameter) scaffold. Mesenchymal stem cells from the bone marrow of young rabbits were grown in culture and then cultured with the PCP scaffold. After 7 weeks in culture, these tracheal implants were transplanted on a 5 × 10 mm tracheal defect in six rabbits, which were evaluated 6 and 10 weeks after the operation.

None of the six rabbits showed any sign of respiratory distress, and endoscopic examination of these tissue engineered tracheae showed that the a normal-looking respiratory epithelium completely covered the regenerated trachea. These trachea also displayed no signs of collapse or blockage.

The tissue engineered tracheae were also scanned and modeled on a computer model (luminal contour). The reconstructed areas of the trachea were the right width and dimensions compared to normal adjacent trachea and were not narrow.

Detailed microscopic tissue examinations of the tissue engineered tracheae showed that the new cartilage was successfully produced by the seeded mesenchymal stem cells and there was only a minimal degree of inflammation or granulation tissue that forms on the surfaces of wounds during the healing process. This shows that the implants did not trigger a massive inflammatory response that damaged resident or implanted tissue.

The outer surfaces of tracheal cells are decorated with tiny beating hairs called cilia that constantly beat to clear particles from the respiratory system. There are also cells that secrete mucus, which acts like fly paper for invading pollutants, particles or microorganisms. in the tissue engineered tracheae, ciliary beating frequency of the regenerated epithelium was not significantly different from the normal adjacent mucosa.

Thus, mesenchymal stem cells from bone marrow seeded on a PCP scaffold successfully restored not only the shape but also the function of the trachea without any signs of graft rejection.

Bones and trachea – mesenchymal stem cells pack a powerful healing punch!!

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

6 thoughts on “MSCs for Tissue Engineered Tracheas and Enhanced Fracture Healing”

  1. Great question. In some cases, osteoporosis results from defects in a patient’s own mesenchymal stem cells. See Mohanty ST1, Kottam L, Gambardella A, Nicklin MJ, Coulton L, Hughes D, Wilson AG, Croucher PI, Bellantuono I.Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis. Arthritis Res Ther. 2010;12(4):R149 and Wang H, Chen Q, Lee SH, Choi Y, Johnson FB, Pignolo RJ. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell. 2012 Aug;11(4):704-13. Therefore in these cases, giving a patient more of their own defective MSCs would probably not work unless those cells could be genetically fixed and then re-administered.

    However, there are plenty of preclinical studies that show that administration of MSCs to osteoporotic animals can increase bone density. See:

    1: Salgado AJ, Oliveira JT, Pedro AJ, Reis RL. Adult stem cells in bone and
    cartilage tissue engineering. Curr Stem Cell Res Ther. 2006 Sep;1(3):345-64.
    Review. PubMed PMID: 18220879.

    2: Wang Z, Goh J, Das De S, Ge Z, Ouyang H, Chong JS, Low SL, Lee EH. Efficacy of
    bone marrow-derived stem cells in strengthening osteoporotic bone in a rabbit
    model. Tissue Eng. 2006 Jul;12(7):1753-61. PubMed PMID: 16889506.

    3: Nakamura T, Naruse M, Chiba Y, Komori T, Sasaki K, Iwamoto M, Fukumoto S.
    Novel Hedgehog Agonists Promote Osteoblast Differentiation in Mesenchymal Stem
    Cells. J Cell Physiol. 2014 Sep 12. doi: 10.1002/jcp.24823. [Epub ahead of print]
    PubMed PMID: 25215620.

    4: Singh L, Brennan TA, Kim JH, Egan KP, McMillan EA, Chen Q, Hankenson KD, Zhang
    Y, Emerson SG, Johnson FB, Pignolo RJ. Long-term functional engraftment of
    mesenchymal progenitor cells in a mouse model of accelerated aging. Stem Cells.
    2013 Mar;31(3):607-11. doi: 10.1002/stem.1294. PubMed PMID: 23193076; PubMed
    Central PMCID: PMC3582822.

    5.Jazedje T, Bueno DF, Almada BV, Caetano H, Czeresnia CE, Perin PM, Halpern S, Maluf M, Evangelista LP, Nisenbaum MG, Martins MT, Passos-Bueno MR, Zatz M. Human fallopian tube mesenchymal stromal cells enhance bone regeneration in a xenotransplanted model. Stem Cell Rev. 2012 Jun;8(2):355-62.

    Therefore there is precedent that such a procedure might work in human patients.

  2. That’s really interesting, and also – given the high rates of mortality and disability resulting from hospitalisations of the elderly for broken bones, and an aging population in the Western World – very relevant in the current medical climate. I notice that one of the studies you cited is from 2006, but I gather from your last comment that there haven’t been any human trials yet. I wonder why that might be.

    1. Getting FDA approval for such tests is really hard because the FDA is really gun-shy about any trials that utilize modified cells. I think that our FDA is working on a regulatory model that is 50 years out of date, that’s where it sits at present.

    1. I think it will. Even in the past four years there have been substantial improvements in tracheal tissue engineering. It seems to me this technology will continue to improve so that by the time you become a resident, it will be available for severely ill patients. The problem is going to be the cost, which will be substantial.

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