Improvements for performing and facilitating the recovery after hematopoietic stem cell transplantation

A technology of hematopoietic stem cells and hematopoietic progenitor cells is applied in the field of promoting hematopoietic recovery after hematopoietic stem cell transplantation, which can solve the problems of unclear comprehensive effects of different estrogens and their underlying mechanisms.

Pending Publication Date: 2022-02-11
CENT DE INVESTIGACIONES ENERGETICAS MEDIOAMBIENTALES Y TECNOLOGICAS O A M P CIEMAT +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Despite these evidences, the full role of different estrogens in the regulation of hematopoietic progenitors and their underlying mechanisms remain unclear

Method used

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  • Improvements for performing and facilitating the recovery after hematopoietic stem cell transplantation
  • Improvements for performing and facilitating the recovery after hematopoietic stem cell transplantation
  • Improvements for performing and facilitating the recovery after hematopoietic stem cell transplantation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1. Increased hematopoietic reconstitution following hematopoietic stem cell transplantation

[0068] Male immunodeficient NSG mice received 2.2Gy irradiation and transplanted 5×10 4 Personal cord blood CD34 + cell. Seventy-two hours later, transplanted animals received 2 [mu]g of estrogen or vehicle (olive oil) per day for 4 days. After 3-4 months, the animals were sacrificed, and the human blood engraftment (graft survival rate) was analyzed by FACS. Human hematopoietic cell populations were identified as hCD45-APC-Cy7 (Biolegend) positive and mouse CD45.1-PE (Biolegend) negative cells.

[0069] Comparisons were made to estrogen-treated or vehicle-treated animals. The results are shown in Table 1:

[0070] Table 1. Human Hematopoietic Reconstitution Percentage (Mean + / - Standard Error of Mean and Number of Mice)

[0071] carrier 26.70+ / -4.19(n＝10) E2 46.05+ / -5.98(n＝13) E4 47.47+ / -6.08(n＝9)

[0072] In addition, human multi-line...

Embodiment 2

[0076] Example 2. Estrogen Enhances Hematopoietic Stem Cell Fraction in Human Hematopoietic Implantation

[0077] To further investigate the role of estrogen in HSCT, FACS analysis of hematopoietic progenitor (hCD34+) and hematopoietic stem cells (hCD34+ / hCD38-) within the human cell population in treated NSG as described in Example 1 was performed. The results are shown in Table 3.

[0078] Table 3. Percentage in human hematopoietic cell population (mean + / - standard error of mean and number of mice)

[0079]

[0080]

[0081] Furthermore, to study long-term effects in HSCT, human CD45+ cells were sorted and transplanted into secondary irradiated female NSG mice. Three months after the second transplantation, artificial hematopoietic engraftment was detected in all animals transplanted with cells from estrogen-treated primary mice.

[0082] Thus, estrogen treatment resulted in a 70% increase in hematopoietic progenitor cells and a doubling of HSCs. More importantly...

Embodiment 3

[0083] Example 3. Estrogen Boosts Limited Dose CD34 in Male Animals + Cell-derived artificial hematopoiesis

[0084] To determine whether estrogen could improve hematopoietic reconstitution in a small number of hematopoietic progenitor cells, male NSGs were irradiated and transplanted with low-dose human cord blood CD34+ (5×10 3 hCD34+). Human implants were analyzed as described in Example 1. The effect of estrogen on promoting the engraftment of low-dose human progenitor cells is shown in Table 4:

[0085] Table 4. Human blood reconstitution percentage (mean + / - standard error of mean and number of mice)

[0086]

[0087] Considering that human hematopoietic cells do not exceed 0.1% in the bone marrow of non-engrafted animals, estrogens (mainly E4) are favorable for achieving successful HSCT with limited doses of HPC. As previously shown, about a quarter of mice had human engraftment rates higher than 0.1%. However, E2 or E4 treatment almost tripled the proportion o...

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Abstract

The present invention provides a method to enhance hematopoietic reconstitution and recovery after hematopoietic stem cell transplantation which is based on the administration of estetrol to the subject that has undergone the transplantation, because estetrol induced an increment in the percentage of hematopoietic cells derived from transplanted donor cells in the recipient. Additionally, estetrol increase the donor contribution in the hematopoietic stem cell compartment. A method for increasing the number of hematopoietic progenitor or stem cells in a culture is also provided, based as well in the addition of estetrol to the culture. As the obtained hematopoietic progenitor or stem cells can be also transplanted, the method increases the availability of donor cells for transplantation. Thus, the invention improves hematopoietic stem cell transplantation in patients.

Description

technical field [0001] The invention provides a method for promoting hematopoietic recovery after hematopoietic stem cell transplantation. More specifically, the present invention relates to a method of enhancing the activity of hematopoietic stem cells with estrogen. Background technique [0002] Hematopoietic stem cells (HSCs) are a rare cell population in the bone marrow of adult mammals, atop a cascade of progenitor cells that gradually become restricted to a few or single blood cell lineages. HSCs are capable of self-renewal (generating more hematopoietic stem cells) and possess the ability to multipotently differentiate into all blood cell lineages (Orkin and Zon, 2008). HSCs are essential for maintaining the lifelong production of all blood cells. HSCs are highly regulated, maintaining homeostasis through a delicate balance between quiescence, self-renewal, and differentiation. Although HSCs rarely divide, they activate self-renewal in response to bone marrow injur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0789A61K35/28A61K31/566
CPCA61K31/565C12N5/0647C12N2501/125C12N2501/145C12N2501/26C12N2501/392C12N2502/1358A61K35/00A61K35/28
Inventor O·昆塔纳 巴斯塔曼特J·C·塞戈维亚 桑斯J·A·博恩 洛瑟罗
Owner CENT DE INVESTIGACIONES ENERGETICAS MEDIOAMBIENTALES Y TECNOLOGICAS O A M P CIEMAT
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