Methods for mobilizing stem cells

Abstract

To provide a soluble P-selectin (sP-sel) interfering the interaction between stem cells and niches to mobilize stem cells from bone marrow.SOLUTION: The mobilization of stem cells with sP-sel can treat a subject in need of preservation, repair, or regeneration of a tissue, or revascularization.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure generally relates to a method for inducing the recruitment of stem cells for wound healing and / or tissue regeneration applications by administration of soluble P-selectin. [Background technology]

[0002] Stem cells (SCs) are defined as cells that possess the unique ability to self-replicate throughout an organism's life and differentiate into various cell types within the body. Two well-known types of stem cells are embryonic stem cells and adult stem cells. Because stem cells can differentiate into a wide variety of cell types, they play a crucial role in wound healing and / or cell / tissue regeneration processes in various tissues and organs. Some stem cells (such as bone marrow stem cells and hematopoietic stem cells) are released from their tissue of origin, circulate through the target circulatory or immune system, and migrate to various organs and tissues, where they mature into terminally differentiated cells. Therefore, enhancing stem cell transport (i.e., release, circulation, homing, and / or migration) can amplify these physiological processes and potentially offer therapeutic options for various medical conditions.

[0003] The recruitment of stem cells from bone marrow to peripheral blood before harvesting is currently used in clinical practice as an alternative to bone marrow in allogeneic stem cell transplantation. AMD3100, a recently approved CXCR4 inhibitor for stem cell recruitment, induces more specific recruitment of cells into circulation than G-CSF by disrupting the CXCR4-SDF1 interaction between bone marrow cells and their microenvironment. For example, US 20180142211 used a CXCR4 antagonist peptide to recruit mesenchymal stem cells into peripheral blood and obtain the cells.

[0004] However, there is still a need to develop drugs for mobilizing stem cells. [Overview of the project]

[0005] This disclosure provides a method for recruiting circulating stem cells in a subject, comprising administering to the subject an amount of soluble P-selectin (sP-sel) effective in recruiting a population of hematopoietic stem cells or progenitor cells for therapeutic application. In one embodiment, soluble P-selectin can interfere with and / or modulate or modulate the interaction between stem cells and the niche.

[0006] This disclosure also provides methods for treating subjects requiring tissue preservation, repair, and / or regeneration, and / or vascular regeneration in the subject, comprising administering to the subject an effective amount of sP-sel to mobilize a population of hematopoietic stem cells or progenitor cells. Enhancement of stem cell transport (i.e., release, circulation, homing, and / or migration) can amplify these physiological processes and provide therapeutic effects for various pathological conditions.

[0007] This disclosure also provides a method for performing allogeneic hematopoietic stem cell transplantation in a patient in need thereof, the method comprising injecting a therapeutically effective amount of allogeneic hematopoietic stem cells into the patient, the hematopoietic stem cells being mobilized from the bone marrow of a human donor into the peripheral blood of a human donor by a method comprising administering an effective amount of sP-sel to the donor.

[0008] According to one embodiment, the stem cells are hematopoietic cells, primordial cells, or bone marrow stem cells.

[0009] In one embodiment, the method further includes administering a second agonist to a subject prior to the administration of sP-sel, after the administration of sP-sel, or simultaneously with the administration of sP-sel. In a further embodiment, the second agonist is selected from the group consisting of G-CSF, GM-CSF, IL-3, GM-CSF / IL-3 fusion protein, FLK-2 / FLT-3 ligand, stem cell factor, IL-6, IL-11, TPO, VEGF, AMD3100, and combinations thereof.

[0010] According to one embodiment, the amount of sP-sel is approximately 10 per kg of body weight per dose. -5The range is from μg to approximately 1.5 mg.

[0011] According to one embodiment, the sP-sel mobilized circulating stem cells (PselMSCs) can produce stem cell-derived extracellular microvesicles.

[0012] In one embodiment, the PselMSC can result in improvement of tissue or organ damage, enhanced repair, improved glucose tolerance, and / or reduction of inflammation. In a further embodiment, the tissue damage is liver damage.

[0013] According to one embodiment, the PselMSC can reform a bone marrow stem cell population or a hematopoietic stem cell population.

[0014] According to one embodiment, the PselMSC can regenerate a bone marrow stem cell population or a hematopoietic stem cell population and can rescue tissue injury, proliferative disorders, inflammatory diseases, immunodeficiency diseases, autoimmune disorders and / or metabolic diseases.

[0015] According to one embodiment, the sP-sel is a naturally occurring sP-sel or a recombinant sP-sel.

[0016] According to one embodiment, the sP-sel can further bind to vesicles and liposomes.

[0017] This disclosure also provides a method for cell therapy in a subject, comprising administering to the subject an amount of sP-sel effective for mobilizing stem cells and an amount of stem cells effective for cell therapy. In one embodiment, the sP-sel and stem cells are administered simultaneously, separately, or intermittently.

[0018] The patent documents or application documents shall include at least one color-coded drawing. A copy of the patent gazette or the publication of the patent application together with the color-coded drawing shall be provided by the authorities upon request and payment of the necessary fees. [Brief explanation of the drawing]

[0019] [Figure 1] Treatment with soluble P-selectin, rather than G-CSF, induced mobilization of CD34+ stem cells in mice. Recombinant mouse soluble P-selectin and G-CSF (Filgrastim®) (both at 0.1 mg / kg body weight) were intravenously injected twice at 24-hour intervals into 8-week-old male C57Bl / 6J experimental mice, and blood samples were collected at 24-hour intervals further (A, overview). The levels of circulating CD34+ mononuclear cells were determined using flow cytometry (FC) (A), and the vehicle (saline) control group was normalized to 100% (B).

[0020] [Figure 2] Treatment with soluble P-selectin, rather than G-CSF, improved thioacetamide (TAA)-induced thrombocytopenia and liver injury in mice. Recombinant mouse soluble P-selectin and G-CSF (Filgrastim®) (both at 0.1 mg / kg body weight) were intravenously injected twice at 24-hour intervals into 8-week-old male C57Bl / 6J experimental mice, and the hepatotoxic drug thrombocytopenia (TAA) was administered at 24-hour intervals further (A, overview). The platelet (PLT) count (B) and the level of circulating liver-specific enzyme aspartate aminotransferase (AST) (C) were analyzed according to the above method 48 hours after TAA treatment.

[0021] [Figure 3] CD34+ cells mobilized by soluble P-selectin can rescue thioacetamide (TAA)-induced liver injury. According to the above method, CD34+ cells mobilized by soluble P-selectin and peripheral blood mononuclear cells (PBMC; monocytes) (both at an injection of 5×106 cells / mouse) were injected together with TAA loading (n = 4; the results were statistically significant (P < 0.05, rmP-sel vs. "non-cell transfer" group and "monocyte" group)).

[0022] [Figure 4]Levels of circulating Lin-Sca-1+c-Kit+ (LSK) stem cells after stimulation with soluble P-selectin. LSK hematopoietic stem cells are a stem cell lineage capable of reconstituting bone marrow stem cells after lethal γ-irradiation. An experimental outline is illustrated (A). C57BL / 6J mice were intravenously injected with soluble P-selectin (0.1 mg / kg) twice a day (n = 5). Peripheral blood (PB) was collected immediately before the first injection and 24 hours later and analyzed using a flow cytometry (FC) assay. The absolute number of LSK cells in peripheral blood was determined (B). Data are reported as mean ± SD. *P < 0.05 (compared with the experimental group before injection).

[0023] [Figure 5] LSK stem cells mobilized by P-selectin rescue the mortality of γ-irradiated mice, indicating the reconstitution of bone marrow hematopoietic stem cells. C57BL / 6J mice that received or did not receive a lethal dose of γ-irradiation used for bone marrow transplantation were the experimental subjects. Those γ-irradiated mice were further treated with a vehicle or LSK stem cells obtained via P-selectin-treated mediated mobilization or G-CSF-treated mediated mobilization. Since both LSK stem cells mobilized by G-CSF and LSK stem cells mobilized by P-selectin can rescue the mortality of γ-irradiated mice, these results indicate that bone marrow hematopoietic stem cells are reconstituted using LSK stem cells prepared by both methods.

[0024] [Figure 6]P-selectin-mobilized CD34+ stem cells (PselMSCs), P-selectin-mobilized CD34+ stem cell-derived microvesicles (PselSCMVs), soluble P-selectin, and soluble P-selectin-conjugated liposomes for the improvement of thioacetamide (TAA)-mediated liver injury. Treatment with PselMSCs and PselSCMVs, soluble P-selectin, and soluble P-selectin-conjugated liposomes can rescue TAA-mediated liver injury, as indicated by the circulating levels of ALT, a hepatocyte-specific expressed enzyme. **P<0.01 (compared to normal / vehicle group); #P<0.05, ##P<0.01 (compared to TAA group). n=6.

[0025] [Figure 7] Treatment with P-selectin-recruited CD34+ stem cells (PselMSCs), P-selectin-recruited CD34+ stem cell-derived microvesicles (PselSCMVs), soluble P-selectin, and soluble P-selectin-binding liposomes to improve glucose tolerance in high-fat diet (HFD) induced diabetic mice. Oral glucose tolerance tests (OGTT) were performed, and plasma glucose levels were determined in different groups of experimental mice. *P<0.05; **P<0.01 (for each HFD group). n=6.

[0026] [Figure 8] Anti-inflammatory effects of P-selectin-mobilized CD34+ stem cells (PselMSCs), P-selectin-mobilized CD34+ stem cell-derived microvesicles (PselSCMVs), soluble P-selectin, and soluble P-selectin-binding liposomes against TAA-induced hepatitis in mice. The degree of TAA-induced inflammation was indicated by circulating TNF-α levels in mice, and the mean TNF-α levels in the normal / vehicle group were normalized to 100%. **P<0.01 (compared to the normal / vehicle group); *P<0.05, **P<0.01 (compared to the TAA group). n=6. [Modes for carrying out the invention]

[0027] If the definition of a term deviates from the commonly used meaning of that term, the applicant shall use the definition provided below unless otherwise specified.

[0028] As used herein and in the appended claims, the singular forms with “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise.

[0029] Where used herein, the use of "or" means "and / or" unless otherwise specified. In the context of multiple dependent claims, the use of "or" refers only to two or more preceding independent or dependent claims, either substituting those claims for the other.

[0030] Where used herein, the terms “one or more” will be readily understood by those skilled in the art, especially when read in the context of their use.

[0031] For the purposes of this specification, the terms “individual,” “subject,” “host,” and “patient” refer to mammals, including, but not limited to, rodents (rats, mice), non-human primates, humans, canids, felines, and ungulates (e.g., horses, cattle, sheep, pigs, goats).

[0032] As used herein, the term “soluble P-selectin” refers to the naturally occurring soluble form of a P-selectin, its recombinant form, or its polymorphic or allelic variant or other isoform. The term also includes modified or unmodified soluble P-selectins (e.g., glycosylated or unglycosylated forms).

[0033] As used herein, the terms “mobilize” and “mobilize” refer to the process by which a population of hematopoietic stem cells or primordial cells is released from a stem cell niche.

[0034] As used herein, the term “niche” refers to the cellular and molecular microenvironment in vivo or in vitro that regulates the function of stem cells in conjunction with their autonomous mechanisms. This includes the control of the balance between quiescence, self-renewal, and differentiation, as well as the involvement of specific programs in response to stress.

[0035] As used herein, the terms “hematopoietic stem cell” or “HSC” refer to stem cells that can differentiate into both myeloid lineages (i.e., monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets and some dendritic cells) and lymphoid lineages (i.e., T cells, B cells, NK cells and some dendritic cells).

[0036] As used herein, the term “subject” refers to any animal, including mammals, birds, reptiles, and amphibians, and in preferred embodiments refers to mammals, including humans, companion animals, food-producing animals, and wild animals.

[0037] As used herein, the term “donor” refers to an object from which one or more cells are isolated prior to administration of those cells or their offspring to a recipient.

[0038] As used herein, the term “effective dose” refers to the amount of one or more activators, such as a soluble P-selectin and / or a second activator described herein that, when administered to a subject, mobilizes a population of hematopoietic stem cells or primordial cells.

[0039] As used herein, the stem cell niche (adult or fetal) refers to the microenvironment within a particular anatomical location where stem cells are found, and which interacts with stem cells to regulate their fate.

[0040] Stem cells can generate new cells to repair tissue damage and therefore have great potential for regenerative medicine. However, stem cells are present in small amounts in tissues, particularly in peripheral blood, making it difficult to harvest or clinically use them. Stem cell recruitment is one method for collecting stem cells from the bone marrow into the bloodstream. In this disclosure, though modest, it has been found that soluble P-selectin (sP-sel) can interfere with the interaction between stem cells and the niche, thus enabling the recruitment of stem cells from the bone marrow. Therefore, by recruiting stem cells with sP-sel, subjects requiring one or more of the following can be treated: tissue preservation, repair, or regeneration, or revascularization.

[0041] P-selectin is a member of the selectin family that localizes to the membranes of α-granules in platelets and Viber-Parade bodies (WP bodies) in endothelial cells. P-selectin is expressed in two distinct forms: one is the "cell surface" form, and the other is the "soluble" form. The former is expressed on the surface of activated platelets or endothelial cells involved in leukocyte inflammation and HSC homing. The latter (i.e., sP-sel) is expressed in plasma almost exclusively only during periods of stress (e.g., hypoxia) in animals / humans (Chang, HH & Sun, DS, Methods of reducing hypoxic stress in a mammal by adminstring soluble P-selectin, U.S. Patent No. 8,377,887 (B1) (2012)). Soluble P-selectin molecules present as monomers in the blood are 3 kDa smaller than P-selectin molecules present as oligomers on the membrane surface. Soluble P-selectin in healthy individuals originates from alternative splicing forms found in endothelial cells and platelets. Surprisingly, in this invention, it has been found that treatment with soluble P-selectin can interfere with the interaction between stem cells and the niche, thereby recruiting stem cells. Hematopoietic stem cells and primordial cells thus recruited can then be extracted from a donor and administered to a patient, in which case these cells can migrate to the hematopoietic stem cell niche and reconstruct a population of damaged or deficient cells in the patient.

[0042] Any form of sP-sel suitable for mobilizing stem cells can be used in this disclosure. Examples of sP-sel in this disclosure include, but are not limited to, naturally occurring sP-sel and recombinant sP-sel. sP-sel can be readily obtained by common techniques, such as isolation from natural sources, purchase from commercial suppliers, or synthesis by molecular biological techniques. When used herein, exemplary p-selectins may also, alternatively, include platelet α-granulosa membrane protein, CD62, granulocyte membrane protein;GRMP; and / or GMP140.

[0043] sP-sel can be used in combination with a second agonist for recruiting stem cells. Examples of the second agonist include, but are not limited to, G-CSF, GM-CSF, IL-3, GM-CSF / IL-3 fusion protein, FLK-2 / FLT-3 ligand, stem cell factors, IL-6, IL-11, TPO, VEGF, AMD3100, and combinations thereof. Preferably, the second agonist is G-CSF. sP-sel and the second agonist can be used simultaneously or sequentially.

[0044] sP-sel can be used in combination with stem cells. sP-sel and stem cells can be administered simultaneously, separately, or intermittently.

[0045] Hematopoietic stem cell transplantation therapy can be administered to patients in need to establish or regenerate one or more blood cell types, such as blood cell lineages that are deficient or incomplete in patients with stem cell dysfunction. Hematopoietic stem cells and primordial cells are pluripotent and can therefore differentiate into many different blood lineages. Different types of blood cells arise from hematopoietic stem cells in lineages called myeloid and lymphoid lineages. Both myeloid and lymphoid lineages are involved in dendritic cell formation. Myeloid cells include megakaryocytes, which range from monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells.

[0046] Hematopoietic stem cells or primordial cells mobilized into the peripheral blood of a subject can be removed from the subject (e.g., recovered or collected) by any suitable technique. For example, hematopoietic stem cells or primordial cells may be removed by blood collection. In some embodiments, hematopoietic stem cells or primordial cells mobilized into the peripheral blood of a subject, as intended herein, may be recovered (i.e., collected) using apheresis. In some embodiments, apheresis may be used to enrich donor blood with mobilized hematopoietic stem cells or primordial cells.

[0047] The sP-sel disclosed herein can be administered typically by injection, such as by local or systemic injection, according to various routes of administration. However, other routes of administration can also be used (e.g., intramuscular, intravenous, intradermal, subcutaneous, etc.). For administration, sP-sel is usually combined with one or more adjuvants appropriate for the indicated route of administration. Furthermore, repeated injections can be performed if necessary. The amount of sP-sel disclosed is approximately 10 per kg of body weight. -5 It is administered in a range of μg to 1.5 mg.

[0048] Circulating stem cells (PselMSCs) mobilized by sP-sel can improve tissue or organ damage, enhance repair, improve glucose tolerance, and / or reduce inflammation. PselMSCs can also reform bone marrow stem cell populations or hematopoietic stem cell populations, and can rescue tissue injury, proliferative disorders, inflammatory diseases, immunodeficiency diseases, genetic disorders, degenerative disorders, autoimmune disorders, and / or metabolic diseases. Examples of proliferative disorders include, but are not limited to, hematological cancers and myeloproliferative disorders. Examples of immunodeficiency diseases include, but are not limited to, congenital and acquired immunodeficiency diseases. Examples of autoimmune disorders include, but are not limited to, juvenile arthritis, ulcerative colitis, type 1 diabetes mellitus, multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), systemic lupus leukemia (SLE), autoimmune lymphoproliferative syndrome (ALPS), and lymphocytic colitis. Examples of metabolic disorders include, but are not limited to, glycogen storage disease, mucopolysaccharidosis, Gaucher disease, Haller's disease, sphingolipidosis, and metachromatic leukodystrophy.

[0049] The extracted hematopoietic stem cells or primordial cells can be reinjected into the patient, thereby allowing these cells to subsequently migrate to hematopoietic tissue, establish proliferative hematopoiesis, and thereby engraft or regenerate cell lineages that are incomplete or deficient in the patient.

[0050] Although the present invention has been described with reference to preferred embodiments and examples, the scope of the invention is not limited to such described embodiments. As will be apparent to those skilled in the art, various modifications and adaptations to the above invention are possible without departing from the spirit and scope of the invention as defined and limited by the appended claims. The following examples are provided to illustrate various embodiments and advantages of the invention and are not intended to limit its scope. [Examples]

[0051] Example 1 CD34+ Cellular soluble P-selectin-mediated mobilization

[0052] According to a previous report (Tajima, F., Sato, T., Laver, JH & Ogawa, M. CD34 expression by murine hematopoietic stem cells mobilized by granulocyte colony-stimulating factor. Blood 96, 1989-1993 (2000)), mouse CD34 + G-CSF-mediated mobilization of cells requires five injections. In this study, the inventors demonstrated that on day 3 (after two G-CSF injections), circulating CD34 in mice was increased. + This showed that no cell induction was observed.

[0053] Recombinant mouse P-selectin (rmP-sel) and granulocyte colony-stimulating factor (G-CSF; Filgrastim®) were intravenously injected into mice after each treatment (0.1 mg / kg body weight). Previously, circulating CD34 + In contrast to the lack of stem cell induction, rmP-sel treatment surprisingly and unexpectedly produced a significant amount of CD34. + Cells were induced by only two injections (see Figure 1A (experimental overview) and Figure 1B). These results suggest that P-selectin is involved in circulating CD34 + This demonstrates that it is far more powerful than G-CSF in terms of cell recruitment.

[0054] Example 2: Soluble P-selectin improved thioacetamide (TAA)-induced thrombocytopenia and liver injury.

[0055] C57BL / 6J mice were injected with TAA to induce acute liver injury, and then treated with or without rm-Psel rescue (Figure 2A, schedule). It was found that pretreatment with rmP-sel twice could rescue the decreased platelet count in peripheral blood to normal levels (Figure 2B). Aspartate aminotransferase (AST) enzyme activity is a standard marker for measuring liver injury. It was also revealed from the data that rmP-sel improved liver injury (Figure 2C). From the data of the present inventors, it was suggested that rmP-sel treatment exerted a tissue protection effect to reduce TAA-induced injury (n = 4; the results were statistically significant (P < 0.05, rmP-sel vs. saline)).

[0056] It has been previously shown that stem cell treatment may have a beneficial effect on improving liver injury. CD34 induced by rmP-Sel + To characterize whether the cells have a tissue protection effect, a transplantation experiment was conducted. From the data of the present inventors, it was not peripheral blood mononuclear cells (PBMC), but CD34 mobilized by P-selectin + Transplantation of stem cells was shown to be able to rescue TAA-induced hepatitis in mice (Figure 3).

[0057] In humans, CD34 stem cells capable of regenerating γ-irradiated bone marrow are mobilized by G-CSF treatment. LSK hematopoietic stem cells in mice are a cell lineage equivalent to CD34 stem cells in humans. To investigate the potential role of P-selectin-mobilized LSK cells in bone marrow regeneration, 1 × 10 + stem cells were transplanted into C57Bl / 6 recipient mice that had received lethal irradiation with γ-rays. + 5Individual soluble P-selectin-mobilized LSK cells (Figure 4) and G-CSF-mobilized LSK cells (Figure 5) were transplanted. The transplants were successfully transplanted, as demonstrated by salvage from 100% lethal gamma irradiation in mice (Figure 5; the survival rate for both the soluble P-selectin-mobilized LSK and G-CSF-mobilized LSK groups was approximately 83%, compared to 100% lethal in the non-transplanted group).

[0058] The protective roles of PselMSCs and PselSCMVs, soluble P-selectin, and soluble P-selectin-binding liposomes were elucidated using a mouse model of TAA hepatitis. Treatment with PselMSCs and PselSCMVs, soluble P-selectin, and soluble P-selectin-binding liposomes significantly relieved the TAA-induced elevation of high circulating alanine aminotransferase (ALT) levels in mice, suggesting that these reagents have a mitigating effect on TAA-induced liver damage (Figure 6).

[0059] Previous studies have shown that adipose-derived mesenchymal stem cells can improve glucose homeostasis in high-fat diet-induced obese mice. However, it remains unclear whether PselMSCs, PselSCMVs, soluble P-selectin, and soluble P-selectin-binding liposomes can improve glucose homeostasis in high-fat diet-induced obese mice. Results from oral glucose tolerance (OGTT) analysis ultimately revealed that PselMSCs, PselSCMVs, soluble P-selectin, and soluble P-selectin-binding liposomes all improved high-fat diet (HFD)-induced glucose tolerance, resulting in a decrease in blood glucose levels in HFD mice (Figure 7).

[0060] Circulating TNF-α levels, which reveal the degree of inflammation, were analyzed in TAA-induced hepatitis mice. The data showed that PselMSC treatment, PselSCMV treatment, soluble P-selectin treatment, and soluble P-selectin-binding liposome treatment all significantly reduced the induction of plasma TNF-α levels by TAA in mice (Figure 8), thus demonstrating that PselMSC, PselSCMV, soluble P-selectin, and soluble P-selectin-binding liposomes all possess anti-inflammatory properties.

Claims

1. A composition for recruiting circulating stem cells and / or producing circulating stem cells (PselMSCs) that are mobilized with soluble P-selectin (sP-sel), wherein the composition comprises soluble P-selectin.

2. The composition according to claim 1, wherein the sP-sel is for interfering with the interaction between the stem cell and the niche.

3. The composition according to claim 1, wherein the stem cells are hematopoietic cells, primordial cells, or bone marrow stem cells.

4. The composition according to claim 1, further comprising the fact that the composition is administered to a subject together with a second activator, the second activator being administered prior to the administration of the composition, after the administration of the composition, or simultaneously in combination with the administration of the composition.

5. The composition according to claim 4, wherein the second activator is selected from the group consisting of G-CSF, GM-CSF, IL-3, GM-CSF / IL-3 fusion protein, FLK-2 / FLT-3 ligand, stem cell factor, IL-6, IL-11, TPO, VEGF, AMD3100, and combinations thereof.

6. The amount of sp-sel mentioned above is 10 per kg of body weight per dose. －５ The composition according to claim 1, wherein the amount is in the range of μg to 1.5 mg.

7. The composition according to claim 1, wherein the PselMSC generates stem cell-derived extracellular microvesicles (PselMSC extracellular microvesicles).

8. The composition according to claim 1, wherein the sP-sel is a naturally occurring sP-sel or a recombinant sP-sel.

9. The composition according to claim 1, wherein the sP-sel further binds to vesicles and liposomes.

10. A composition for treating liver tissue or organ damage, thrombocytopenia, hepatitis, gamma radiation, and / or glucose tolerance in a subject requiring treatment, comprising sP-sel for mobilizing circulating stem cells.

11. The composition according to claim 10, administered together with a therapeutically effective amount of circulating stem cells.

12. The composition according to claim 11, wherein the composition and the circulating stem cells are administered simultaneously, separately, or intermittently.

Images