Limited proliferation of stem cells surviving alkylating agents

Botnick, Leslie E.; Hannon, Eileen C.; Hellman, Samuel

doi:10.1038/262068a0

Cited by 66 publications

(23 citation statements)

References 7 publications

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“…These observations strongly indicated a very primitive nature of the precursors for the stem cell colonies. There has been indirect evidence for the heterogeneous nature and the hierarchy of hemopoietic stem cells (14)(15)(16)(17)(18). In this model, the early stem cells will be less committed to differentiation and have a higher self-renewal capacity than the stem cells in lower states in the hierarchy, which would be more committed to differentiation and have a lower self-renewal potential.…”

Section: Discussionmentioning

confidence: 99%

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Identification in culture of a class of hemopoietic colony-forming units with extensive capability to self-renew and generate multipotential hemopoietic colonies.

Nakahata¹,

Ogawa²

1982

Proc. Natl. Acad. Sci. U.S.A.

292

106

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Mouse marrow and spleen cells formed colonies consisting of 40-1,000 blast cells after 16 days of incubation in methylcellulose culture in the presence of medium conditioned by pokeweed mitogen-stimulated mouse spleen cells. These colonies could be distinguished from other hemopoietic colonies in situ by the complete absence of signs of terminal differentiation. Replating of these colonies (tentatively named stem cell colonies) revealed their self-renewal capacity and the extensive ability to generate secondary colonies, many of which were multipotential hemopoietic colonies. Some of the colonies revealed 100% replating efficiencies. Analyses ofindividual stem cells colonies revealed concurrent and high incidences of spleen colony-forming units and the macroscopic granulocyte-erythrocyte-macrophage-megakaryocyte colony-forming units (CFU-GEMM) in culture. Replating comparison between the stem cell colonies and GEMM colonies strongly indicated that the progenitors for the stem cell colonies are higher in the hierarchy of stem cell differentiation than are CFU-GEMM. Quantitation of stem cell colonies provides an assay for the class of primitive hemopoietic progenitors described here.

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Section: Discussionmentioning

confidence: 99%

“…* Abbreviations of the types of colonies are as in Table 1. those forming GEMM colonies, because on the average only 223 cells were produced after 16 days of culture. In contrast, the macroscopic GEMM colonies attained an average size of 2.2 x 105 cells after 10 days in culture.…”

Section: Discussionmentioning

confidence: 99%

Identification in culture of a class of hemopoietic colony-forming units with extensive capability to self-renew and generate multipotential hemopoietic colonies.

Nakahata¹,

Ogawa²

1982

Proc. Natl. Acad. Sci. U.S.A.

292

106

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“…Finally, the present estimate is predicated on the assumption that all CFU-S can generate CFU-S. Although prolonged self-renewal may be restricted to a small subset of the CFU-S population (15,16), our analysis revolves around the point ofinflection from exponential growth, which occurs after only five or so divisions. Apropos this, a majority of spleen colonies have been shown to contain multiple CFU-S despite great pressure for differentiation in xirradiated mice (17,18) and such pressure should be considerably less in unirradiated W/W" recipients.…”

Section: Resultsmentioning

confidence: 99%

Partitioning of bone marrow into stem cell regulatory domains.

Maloney¹,

Lamela²,

Banda³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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To examine the hypothesis that bone marrow consists of discrete stem cell regulatory volumes or domains, we studied spleen colony-forming unit (CFU-S) population growth kinetics in unirradiated WBB6F1-W/Wv mice receiving various doses of +/+ bone marrow cells. Assay of femoral marrow CFU-S content in the eight recipient dose groups revealed a family of growth curves having an initial dose-independent exponential phase and a subsequent dose-dependent deceleration phase. CFU-S content at the growth transition (inflection point) was not a simple linear function of inoculum dose but was shown rather to reflect a random distribution of initially seeded donor CFU-S in discrete volumes of recipient bone marrow. The inoculum dose resulting in a mean of 1 CFU-S per bone marrow sampling unit was estimated to be 17 x 10(6) bone marrow cells, corresponding to a total marrow uptake of approximately 5100 CFU-S (based on a seeding efficiency factor of 10%). If we assume single-hit kinetics, it follows that the recipient W/Wv bone marrow may contain approximately 5100 domains in which stem cell proliferation is geared to the density of the stem cell population. When the various inocula were corrected for multiple seeding in a given domain, the mean inflection point per domain was similar and indicative of five or so divisions before departure from exponential growth at approximately 20% of final CFU-S content 8 days after bone marrow injection. The partitioning of bone marrow into highly localized functional units is consistent with the putative regulatory role of short-range interactions between stem cells and essential stromal elements.

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“…That such a defect arose primarily from damage to hematopoietic stem cells was evident after normal, unmanipulated and transplanted marrow cells corrected the hematopoietic defect in busulfan treated mice (2). Several years later Botnick, Hannon, and Hellman observed hematopoietic failure after exposure of mice to alkylating agents, phenylalanine mustard, busulfan and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) (3,4). They ascertained that this effect was a differential one, varying with the use of different drugs and possibly affecting differing stem cell compartments (5).…”

Section: Introductionmentioning

confidence: 99%

Long term hematopoeitic damage after chemotherapy and cytokine

Gardner¹

1999

Front Biosci

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Limited proliferation of stem cells surviving alkylating agents

Cited by 66 publications

References 7 publications

Identification in culture of a class of hemopoietic colony-forming units with extensive capability to self-renew and generate multipotential hemopoietic colonies.

Identification in culture of a class of hemopoietic colony-forming units with extensive capability to self-renew and generate multipotential hemopoietic colonies.

Partitioning of bone marrow into stem cell regulatory domains.

Long term hematopoeitic damage after chemotherapy and cytokine

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