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Methods and compositions for producing germ cells from bone marrow derived germline stem cells

a technology of germ cells and compositions, which is applied in the direction of drug compositions, non-embryonic pluripotent stem cells, sexual disorders, etc., can solve the problems of failure to provide evidence of germinal epithelium and the inability of bone marrow derived cells to successfully repopulate, etc., to enhance or restore fertility, restore gonadal function, and replenish or expand germ cell reserves

Inactive Publication Date: 2006-01-12
THE GENERAL HOSPITAL CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] It has now been shown that bone marrow derived germline stem cells can repopulate the germline of reproductive organs, and thus restore gonadal function. Methods of the invention relate to the use of bone marrow derived germline stem cells and their progenitors to, among other things, replenish or expand germ cell reserves of the testes and ovary, to enhance or restore fertility, and in females, to ameliorate symptoms and consequences of menopause.

Problems solved by technology

However, it remains unclear whether the precursors of germ cells are confined exclusively to the ovaries or whether extra-ovarian sites in the body, contain precursors having the ability to form germ cells.
These experiments failed to provide evidence that germinal epithelium of the test rat could be repopulated to reinitiate spermatogenesis upon injection of bone marrow cells obtained from the donor rat.
Therefore, it was not believed that bone marrow derived cells could successfully repopulate the germline of the mammalian gonads.

Method used

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  • Methods and compositions for producing germ cells from bone marrow derived germline stem cells
  • Methods and compositions for producing germ cells from bone marrow derived germline stem cells
  • Methods and compositions for producing germ cells from bone marrow derived germline stem cells

Examples

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example 1

Extra-Ovarian Female Germline Progenitor Cell Reservoirs

[0213] The restricted pattern of SSEA1 expression in the adult mouse ovary (FIG. 1a, b) suggested that the number of germline stem cells / progenitors thereof is relatively small. However, this would be incongruous with recent studies indicating that germline stem cells must offset an extremely robust rate of oocyte death for the gonads to remain functional throughout reproductive life (Johnson, J. et al (2004) Nature 428, 145-150) as well as with the ability of adult mouse ovaries to rapidly generate hundreds of new primordial oocyte-containing follicles. For details, see U.S. Application Ser. No. ______, filed on May 17, 2005 as Attorney Docket No. 51588-62054, the contents of which are herein incorporated by reference. Accordingly, the possibility that a larger germline stem cell reservoir exists somewhere outside of the ovaries was considered. The first clue in this regard was provided by the location of SSEA1+ cells in the ...

example 2

Bone Marrow Transplantation Reverses Pathological Ovarian Failure

[0222] To assess the functional capacity of bone marrow-derived germ cells to produce new oocytes, bone marrow was isolated from adult wild-type female mice and transplanted using standard procedures into recipient adult females sterilized by treatment with a combination of cyclophosphamide and busulphan to destroy the existing pre- and post-meiotic germ cell pools prior to BMT.

[0223] Bone marrow was harvested from adult (6-10 weeks of age) wild-type C57BL / 6 female mice on the day of transplantation, and 2-5×107 cells were injected intravenously via the tail vein into recipients using standard procedures. To prepare recipients, female mice received 0.5 mg anti-CD4 antibody (GK1.5) (Dialynas, D. P. et al. (1984) J. Immunol. 131, 2445-2451) and 1 mg anti-CD8 antibody (2.43) (Sarmiento, M. et al. (1980) J. Immunol. 125, 2665-2672) one week prior to a second injection of each antibody along with 120 mg kg−1 cyclophospham...

example 3

Bone Marrow Transplantation Rescues Oocyte Production in Atm Mutants

[0226] Atm− / − (homozygous null) mice, created by targeted inactivation of the Atm gene, display many of the hallmarks of the Ataxia-telangiectasia syndrome in humans, including growth retardation, defects in T lymphocyte maturation and infertility (Bagley et al. (2004) Blood 12: 1). Atm-deficient male and female mice have been shown to be infertile due to the complete loss of the production of mature gametes, i.e., spermatozoa and oocytes (Barlow, C. et al. (1996) Cell 86: 159). These gametogenesis defects in mutant mice lacking Atm result from apoptosis and degeneration of the developing gametes that exhibit aberrant early stages of meiosis, detected as early as the leptotene stage (Barlow, C. et al. (1998) Development 125: 4007). Ovaries from Atm-deficient females were shown to be completely barren of oocytes and follicles by at least 11 days of age postpartum (Barlow, C. et al. (1998) Development 125: 4007).

[02...

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Abstract

The present invention relates to the use of bone marrow derived germline stem cells and their progenitors, methods of isolation thereof, and methods of use thereof.

Description

RELATED APPLICATIONS / PATENTS & INCORPORATION BY REFERENCE [0001] This application claims priority to U.S. Application Ser. No. 60 / 572,222, filed on May 17, 2004 as Attorney Docket No. 910000-3073, U.S. Application Ser. No. 60 / 574,187, filed on May 24, 2004 as Attorney Docket No. 910000-3074, and U.S. Application Ser. No. 60 / 586,641, filed on Jul. 9, 2004 as Attorney Docket No. 910000-3076, the contents each of which are incorporated herein by reference.STATEMENT OF POTENTIAL GOVERNMENT INTEREST [0002] The United States government may have certain rights in this invention by virtue of grant numbers R01-AG12279 and R01-AG24999 from the National Institute on Aging of the National Institutes of Health.[0003] Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; “application cited documents”), and each of the PCT and foreign applications or paten...

Claims

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Application Information

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IPC IPC(8): A01K67/027C12N5/06A61K35/12C12N5/074
CPCC12N5/0611A61K2035/124A61P15/08A61P15/12A61P15/16A61P15/18A61P35/00C12N5/0634C12P21/06A61K35/28A61B17/43A61K35/14C12N5/0609C12N2506/11
Inventor JOHNSON, JOSHUATILLY, JONATHAN L.
Owner THE GENERAL HOSPITAL CORP
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