Multiple mesodermal lineage differentiation potentials for adipose tissue-derived stromal cells and uses thereof

Abstract

The invention relates to methods and compositions for the differentiation of stromal cells from adipose tissue into hematopoietic supporting stromal cells and myocytes of both the skeletal and smooth muscle type. The cells produced by the methods are useful in providing a source of fully differentiated and functional cells for research, transplantation and development of tissue engineering products for the treatment of human diseases and traumatic tissue injury repair.

Description

[0001] This Application claims the benefit of U.S. Provisional Application No. 60 / 149,849 filed on Aug. 19, 1999.[0002] This invention relates to methods and compositions for the differentiation of stromal cells from adipose tissue into hematopoietic supporting stromal cells and myocytes of both the skeletal and smooth muscle types.BACKGROUND OF INVENTION[0003] The neonatal period in human development is characterized by the presence of "stem" cells with the potential to develop along multiple differentiation pathways. The terminal differentiation of these cells is determined by cytokine and hormonal cues which co-ordinate organogenesis and tissue architecture. Murine embryonic stem cells have been isolated and studied extensively in vitro and in vivo. Using exogenous stimuli in vitro, investigators have induced ES cell differentiation along multiple lineage pathways. These include neuronal, B lineage lymphoid, and adipocytes (Dani et al. (1997) J. Cell Sci. 110: 1279; Remoncourt et...

AI Technical Summary

Benefits of technology

[0045] The adipose tissue derived stromal cells may be stably or transiently transfected or transduced with a nucleic acid of interest using a plasmid, viral or alternative vector strategy. Nucleic acids of interest include, but are not limited to, those encoding gene products which; (1) enhance the growth, differentiation, maturation and proliferation of hematopoietic cell lineages; examples include osteoprotegerin ligand which induces osteoclast development, interleukin 7, which induces B lineage lymphocyte development, erythropoietin, which induces erythrocyte development, and thrombopoietin, which induces platelet development; (2) enhance the differentiation of skeletal muscle; examples include myoD and myogenin, transcription factors which promote myotubule formation and expression of skeletal muscle specific genes; (3) enhance the growth, differentiation and maturation of smooth muscle cells; examples include transforming growth factor .beta., which induces smooth muscle proliferation and extracellular matrix production.

[0050] Another object of the invention is to provide methods for the identification and study of compounds that enhance or inhibit the differentiation of adipose tissue derived stromal cells into either hematopoietic supporting stromal cells, skeletal muscle myocytes, or smooth muscle myocytes. Compounds which enhance differentiation. (a) hematopoietic supporting stromal cell function may be of value in the treatment of blood dyscrasias characterized by decreased production of circulating blood cells and improve recovery of patients following high dose chemotherapy; (b) skeletal muscle myocytes may be of value in the treatment of musculoskeletal diseases secondary to hereditary defects or trauma; or (c) smooth muscle myocytes may be of value in the treatment of smooth muscle defects, including those of the urinary bladder (bladder wall), gastrointestinal tract (colon, small intestine), and genital system (vaginal). Conversely, compounds which inhibit differentiation of (a) hematopoietic supporting stromal cells may be of value in the treatment of blood dyscrasias characterized by overproduction of circulating blood cells, such as polycythemia vera; (b) skeletal muscle may be of value in the treatment of soft tissue tumors of skeletal muscle origin, such as rhabdomyosarcomas; and (c) smooth muscle may be of value in the treatment of soft tissue tumors of smooth muscle origin, such as leiomyosarcomas.

Problems solved by technology

The major limitations to the use of these cells are the difficulty and risk attendant upon bone marrow biopsy procedures and the accompanying loss of memory B cells and hematopoictic stem cells with present harvesting procedures.

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