Hematopoietic stem cells

Details Hematopoietic stem cells Hematopoietic stem cells

1998-12-04

2003-03-25

Saunders, David (Department: 1644)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S002000, C435S372000

Reexamination Certificate

active

06537807

ABSTRACT:

TECHNICAL FIELD
The present invention relates to hematopoietic stem cells and to methods of treating diseases and disorders, including genetic diseases and disorders and infectious diseases, using same. The invention additionally relates to methods of identifying agents that promote growth, engraftment or differentiation of stem cells.
BACKGROUND
The ability to isolate and manipulate hematopoietic stem cells (HSC) for the purposes of gene therapy and transplantation has drawn intensified interest in recent years (Emerson, Blood 87:3082 (1996); Karlsson, Blood 78:2481 (1991)). Functionally, the most primitive hematopoietic stem cells have extensive potential for self renewal and can give rise to all blood cell lineages. Currently, however, the phenotype of the most primitive human hematopoietic stem cells remains unclear. Primitive human hematopoietic progenitors with extensive potential for self renewal and multilineage development have been characterized by numerous groups using both in vitro assays and chimeric animal models. These studies suggest that the most primitive human HSC express the CD34 surface marker (CD34
+
), lack obvious lineage commitment markers (Lin
−
) and express low to undetectable levels of other cell surface markers including CD38, CD71 CD45RA, and Thy-1 (Terstaypen et al, Blood 77:1218 (1991); Landsdorp et al, J. Exp. Med. 178:787 (1993); Cicuttini et al, Growth Factors 10:127 (1994); De Bruyn et al, Stem Cells 13:281 (1995); Di Giusto et al, Blood 84:421 (1994); Hao et al, Blood 86:374 (1995); Huang et al, Blood 83:1515 (1994); Muench et al, Blood 83:3170 (1994); Rusten et al, Blood 84:1473 (1994)). Despite this evidence, to date there have been no human transplant studies to formally determine the phenotype of the most primitive human hematopoietic stem cells.
Recently, three studies using long term murine bone marrow transplant models have indicated that there are populations of primitive HSC that express low to undetectable amounts of CD34 (CD34
lo−
cells) and that are capable of durably generating lymphoid and myeloid lineages following their transplantation. Osawa et al (Science 273:242 (1996)) demonstrated that a single Lin
−
c-kit
+
Ly6A/Sca-1
+
CD34
lo/
−
cell could result in long term hematopoietic reconstitution in recipient mice. Jones et al (Blood 88:487 (1996)) identified a population of small Lin
−
CD34
lo/−
AA4.1
−
cells that expressed high levels of aldehyde dehydrogenase that were capable of durably generating lymphoid and myeloid lineages following engraftment. Morel et al (Blood 88:629a (1996)) demonstrated that Lin
−
thy-1
lo
Ly6A/Sca-1
+
CD34
lo/
−
cells contain high proportions of long-term repopulating HSCs.
The present invention is based, at least in part, on the finding that human CD34
−
HSC exist and that these cells, designed CD7
+
CD34
−
Lin
−
cells, possess properties consistent with primitive pluripotent cells.
SUMMARY OF THE INVENTION
The present invention relates to hematopoietic stem cells, designated CD7
+
CD34
−
Lin
−
cells. The invention further relates to methods of treating diseases and disorders using such cells. Examples of diseases that can be treated with the cells of the invention include both genetic and infectious diseases. The invention also relates to methods of identifying agents that can be used to promote growth and engraftment of stem cells, as well as the differentiation of such cells.
Objects and advantages of the present invention will be clear from the description that follows.


REFERENCES:
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patent: 5643741 (1997-07-01), Tsukamoto et al.
patent: WO 96/39489 (1996-12-01), None
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Bárcena et al, “Phenotypic and Functional Analysis of T-Cell Precursors in the Human Fetal Liver and Thymus: CD7 Expression in the Early Stages of T-and Myeloid-Cell Development”, Blood 82(11):3401-3414 (1993).
Mossalayi et al, “Human Marrow CD7+CD2-CD34-Cells Are Committed to T Cell Lineage: Possible Filiation From Earlier 34+CD7+Precursor”, J. Cell Biochem. Supp 16C:79 (1992), Abstract No. M232.
Nakauchi, “Hematopoietic stem cells: Are they CD34-positive or CD34-negative?”, Nature Medicine 4(9):1009-1010 (1998).
Bhatia et al, “A newly discovered class of human hematopoietic cells with SCID-repopulating activity”, Nature Medicine 4(9):1038-1045 (1998).
Bonnet et al, “Development of conditions for the ex vivo culture of a novel CD34 population of primitive human hematopoietic repopulating cells”, Blood 90(10) Suppl 1 (Part 1 of 2), Nov. 15, 1997, Abstract No. 703.
Hansteen et al, “CD34+, but not CD34+ cells with the human hoescht 33342 ′side popu . . . possess primitive pluripotent progenitor activity”, Blood 90(10) Suppl 1 (Part 1 of 2), Nov. 15, 1997, Abstract No. 704.
Punzel et al, “Human bone marrow (BM) CD34+/HLA-DR- cells expressing CD2 and/or contain primitive myeloid LTCIC with similar growth characteristics as lineage depleted progenitors”, Blood 90(10) Suppl 1 (Part 1 of 2), Nov. 15, 1997, Abstract No. 705.
Storms et al, “Novel CD7+ hematopoietic cells isolated from human umbilical cord blood”, Blood 90(10) Suppl 1 (Part 1 of 2), Nov. 15, 1997, Abstract No. 2130.
Storm et al, “Characterization of Hematopoietic Cells Isolated From Human Umbilical Cord Blood Using Hoechst 33342”, Blood 88 (10 sup 1):157 (1996).
Goodell, M.A., et al. Isolation and Functional Properties of Murine Hematopoietic Stem Cells that are ReplicatingIn Vivo, J. Exp. Med. vol. 183, 1996, pp. 1797-1806.

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