Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin In Vivo

Amelia Bartholomew, Sheila Patil, Alastair Mackay, Mary Nelson, Diana Buyaner, Wayne Hardy, Joseph Mosca, Cord Sturgeon, Mandy Siatskas, Nadim Mahmud, Karen Ferrer, Robert Deans, Annemarie Moseley, Ronald Hoffman, Steven M. Devine

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

Human mesenchymal stem cells (MSCs) are capable of differentiating into multiple mesenchymal lineages including chondrocytes, osteocytes, adipocytes, and marrow stromal cells. Using a nonhuman primate model, we evaluated nonhuman primate MSCs as targets for gene therapy. Baboon MSCs (bMSCs) cultured from bone marrow aspirates appeared as a homogeneous population of spindle-shaped cells. bMSCs were capable of differentiating into adipocytes and osteocytes in vitro and chondrocytes in vivo. bMSCs were genetically modified with a bicistronic vector encoding the human erythropoietin (hEPO) gene and the green fluorescent protein (GFP) gene. Transduction efficiencies ranged from 72 to 99% after incubation of MSCs with retro-viral supernatant. Transduced cells produced from 1.83×105 to 7.12×105 mIU of hEPO per 106 cells per 24 hr in vitro before implantation. To determine the capacity of bMSCs to express hEPO in vivo, transduced bMSCs were injected intramuscularly in NOD/SCID mice. In a separate experiment, transduced bMSCs were loaded into immunoisolatory devices (IIDs) and surgically implanted into either autologous or allogeneic baboon recipients. Human EPO was detected in the serum of NOD/SCID mice for up to 28 days and in the serum of five baboons for between 9 and 137 days. NOD/SCID mice experienced sharp rises in hematocrit after intramuscular injection of hEPO-transduced bMSCs. The baboon that expressed hEPO for 137 days experienced a statistically significant (p<0.04) rise in its hematocrit. These data demonstrate that nonhuman primate MSCs can be engineered to deliver a secreted and biologically active gene product. Therefore, human MSCs may be an effective target for future human gene therapy trials.

Original languageEnglish (US)
Pages (from-to)1527-1541
Number of pages15
JournalHuman Gene Therapy
Volume12
Issue number12
DOIs
StatePublished - Aug 10 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Bartholomew, A., Patil, S., Mackay, A., Nelson, M., Buyaner, D., Hardy, W., Mosca, J., Sturgeon, C., Siatskas, M., Mahmud, N., Ferrer, K., Deans, R., Moseley, A., Hoffman, R., & Devine, S. M. (2001). Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin In Vivo. Human Gene Therapy, 12(12), 1527-1541. https://doi.org/10.1089/10430340152480258