The Oncogenesis of Glial Cells in Diffuse Gliomas and Clinical Opportunities / 神经科学通报·英文版

Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.

Spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium

Molecular knowledge of human gastric corpus epithelium remains incomplete. Here, by integrated analyses using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) techniques, we uncovered the spatially resolved expression landscape and gene-regulatory network of human gastric corpus epithelium. Specifically, we identified a stem/progenitor cell population in the isthmus of human gastric corpus, where EGF and WNT signaling pathways were activated. Meanwhile, LGR4, but not LGR5, was responsible for the activation of WNT signaling pathway. Importantly, FABP5 and NME1 were identified and validated as crucial for both normal gastric stem/progenitor cells and gastric cancer cells. Finally, we explored the epigenetic regulation of critical genes for gastric corpus epithelium at chromatin state level, and identified several important cell-type-specific transcription factors. In summary, our work provides novel insights to systematically understand the cellular diversity and homeostasis of human gastric corpus epithelium in vivo.

Atorvastatin ameliorates viral burden and neural stem/ progenitor cell (NSPC) death in an experimental model of Japanese encephalitis

Japanese encephalitis virus, a neurotropic flavivirus, causes sporadic encephalitis with nearly 25% fatal casereports. JEV infects neural stem/progenitor cells (NSPCs) and decreases their proliferation. Statin, a commonlyused class of cholesterol lowering drug, has been shown to possess potent anti-inflammatory and neuroprotective effects in acute brain injury and chronic neurodegenerative conditions. Here, we aimed to check theefficacy of atorvastatin in alleviating the symptoms of Japanese encephalitis (JE). Using BALB/c mouse modelof JEV infection, we observed that atorvastatin effectively reduces viral load in the subventricular zone (SVZ)of infected pups and decreases the resultant cell death. Furthermore, atorvastatin abrogates microglial activation and production of proinflammatory cyto/chemokine production post JEV infection in vivo. It alsoreduced interferon-b response in the neurogenic environs. The neuroprotective role of atorvastatin is againevident from the rescued neurosphere size and decreased cell death in vitro. It has also been observed that uponatorvastatin administration, cell cycle regulatory proteins and cell survival proteins are also restored to theirrespective expression level as observed in uninfected animals. Thus the antiviral, immunomodulatory andneuroprotective roles of atorvastatin reflect in our experimental observations. Therefore, this drug broadens apath for future therapeutic measures against JEV infection.

Role of N-acetyl cysteine on bone marrow-derived hematopoietic stem/progenitor cell cryopreservation: Outcome on the oxidative stress-mediated cryodamage and repopulation Capacity into hematopoietic lineages

Cryopreservation of hematopoietic stem/progenitor cells (HSPCs) is associated with oxidative stress-mediatedcryodamage, hence compromising the therapeutic potency. The roles of N-acetyl cysteine (NAC) on the oxidativestress-mediated cryodamage and repopulation capacity of HSPCs into myeloid, erythroid, and pre-B lymphoidprogenitors were investigated. Mice bone marrow-derived HSPCs were cultured for 24 hours, followed bycryopreservation at 1 × 106/ml cells in cryomedium containing 10% dimethyl sulfoxide with NAC (0.25, 0.5, or 2.0µM) or without for 48 hours, 2 weeks, and 4 weeks at −80°C. Cryopreservation significantly reduced cell viability atpost-thawed (p < 0.05) with long-term cryopreservation conferred a greater cell recovery. NAC improved the bonemarrow-derived HSPC viability (p < 0.05) at 0.5 and 2.0 µM after 48 hours of cryopreservation. Cryopreservationlowered the malondialdehyde level (p < 0.05) although glutathione, superoxide dismutase, and protein carbonyl levelswere not significantly affected. Repopulation capacity of HSPCs into myeloid–erythroid progenitors was greatlyreduced (p < 0.05) after 4 weeks of cryopreservation as compared to precryopreservation group. Meanwhile, NACsupplementation showed no remarkable effect on oxidative stress-mediated cryodamage and repopulation capacity ofHSPCs. Conclusively, the cryoprotective role of NAC on the cryopreservation of HSPCs deserves further investigation

Novel insights into cell cycle regulation of cell fate determination / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.

Novel insights into cell cycle regulation of cell fate determination / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The stem/progenitor cell has long been regarded as a central cell type in development, homeostasis, and regeneration, largely owing to its robust self-renewal and multilineage differentiation abilities. The balance between self-renewal and stem/progenitor cell differentiation requires the coordinated regulation of cell cycle progression and cell fate determination. Extensive studies have demonstrated that cell cycle states determine cell fates, because cells in different cell cycle states are characterized by distinct molecular features and functional outputs. Recent advances in high-resolution epigenome profiling, single-cell transcriptomics, and cell cycle reporter systems have provided novel insights into the cell cycle regulation of cell fate determination. Here, we review recent advances in cell cycle-dependent cell fate determination and functional heterogeneity, and the application of cell cycle manipulation for cell fate conversion. These findings will provide insight into our understanding of cell cycle regulation of cell fate determination in this field, and may facilitate its potential application in translational medicine.

Current research on molecular mechanism of ionizing radiation-induced neurogenesis disorders / 中华放射肿瘤学杂志

With the development of modern radiotherapy techniques,radiotherapy has been widely used in the multimodality therapy for various malignant tumors,including head and neck cancers such as nasopharyngeal cancer and laryngeal cancer.A combination of surgery and radiochemotherapy significantly improves patients' cure rate and survival time;however,with the increase in survival time,some patients receiving radiotherapy develop marked cognitive impairment.Ionizing radiation-induced cognitive impairment mainly nanifests as hippocampus-dependent cognitive impairment,which is associated with inhibited hippocampal neurogenesis due to ionizing radiation.Therefore,it is necessary to investigate the mechanisms of the inhibition of hippocampal neurogenesis by ionizing radiation.This article reviews the molecular mechanism of neurogenesis disorders induced by ionizing radiation.

Gene expressions of the human intrahepatic cholangiocarcinoma RBE cell line / 中华肝胆外科杂志

Objective To analyze the differentially expressed genes between the NCAM + c-Kit +RBE and NCAM-c-Kit-RBE of intrahepatic cholangiocarcinoma (ICC) cell lines,and to screen out the differentially expressed genes that are related to the stem cell signaling pathways.Methods Magnetic activated cell sorting was used to isolate the NCAM + c-Kit +/NCAM-c-Kit-subset cells,and then Agilent Whole Human Genome Microarray Kit was used to test the difference in gene expressions between the NCAM + cKit + and NCAM-c-Kit-subset cells.The difference in gene expressions related to the stem cell signaling pathways was analyzed by the SAS system.The result of the microarray was further confirmed by RT-PCR.Results The total differentially expressed genes which could be found through gene microarray were 7270 [foldchange(fc) ≥2 or fc ≤0.5].Compared with the NCAM-c-Kit-RBE,3572 genes were upregulated while 3698 genes were downregulated.The differences in gene expressions related to the stem cell signaling pathways were 421 (fc ≥2 or fc ≤ 0.5),among which 231 genes were upregulated while 190 genes were downregulated.Conclusions High-flux microarray could be used to screen out lots of differentially expressed genes between the NCAM + c-Kit + and NCAM-c-Kit-RBE cells.The differences in gene expression in the stem cell signaling pathways could also be further analyzed using the SAS system.

When morphogenetic proteins encounter special extracellular matrix and cell-cell connections at the interface of the renal stem/progenitor cell niche / 대한해부학회지

Reciprocal exchange of morphogenetic proteins between epithelial and mesenchymal cells in a stem/progenitor cell niche results in formation of a nephron. To maintain diffusion of morphogenetic proteins, it is assumed that a close contact exists between involved cells. However, recent publications underline that both types of stem/progenitor cells are separated by a striking interface. To explore this microarchitecture in detail, neonatal rabbit kidneys were fixed in traditional glutaraldehyde (GA) solution for transmission electron microscopy. For contrast enhancing specimens were fixed in GA solution including cupromeronic blue, ruthenium red or tannic acid. To record same perspectives, embedded blocks of parenchyma were cut in exactly orientated vertical and transverse planes to lining collecting ducts. Electron microscopy of specimens fixed by traditional GA solution illustrates a spatial separation of stem/progenitor cells and an unobstrusively looking interface. In contrast, advanced fixation of specimens in GA solution including cupromeronic blue, ruthenium red and tannic acid unmasks earlier not visible extracellular matrix. In addition, projections of mesenchymal cells covered by matrix cross the interface to contact epithelial cells. Surprisingly, the end of a mesenchymal cell projection does not dangle but is enclosed in a fitting sleeve and connected via tunneling nanotubes with the plasma membrane of an epithelial cell. Regarding this complex ensemble the question is to what extent illustrated cell-cell connections and extracellular matrix are involved in communication and transmission of morphogenetic proteins during induction of a nephron.

Valproic Acid Increases Expression of Neuronal Stem/Progenitor Cell in Spinal Cord Injury

OBJECTIVE: This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model. METHODS: Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively. RESULTS: Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group. CONCLUSION: Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI.

The effect of adenovirus mediated LIF and OSM co-expressing on proliferation and differentiation of umbilical cord blood CD34+ hematopoietic stem/progenitor cell / 中华微生物学和免疫学杂志

Objective To establish Ad-LIF-OSM transgenic feeder cells for the expansion of CD34+ hematopoietic stem/progenitor cell and tentatively study its effect in expansion and differentiation of cord blood hematopoietic stem cell(HSC) in vitro.Methods In the foundation of pAdTrack-CMV-LIF-polyA+promoterΔ,the OSM gene was inserted to the vector plasmid.Then we structure the transfer plasmid pAdTrack-CMV-LIF-polyA+promoterΔ-OSM.The transfer vector and backbone vector were further cotransfected for homologous recombination. The result pAdEasy-1-pAdTrack-CMV-LIF-polyA + promoterΔ-OSM homologous recombination plasmid were transfected into the human embryonic kidney 293 (QBI-293A) cells,leading to formation of the recombinant adenviruses Ad-LIF-OSM which co-expressing LIF and OSM.Infect the feeder layer cells with groups of Adenovirus,detection the expressing of LIF and OSM in WI-38 cells by RT-PCR and ELISA.Compares the stem cells differentiation and proliferation of the different experimental groups in vitro by transwell and cell counting.Results The sequencing results show that the OSM genes were anastomotic in Ad-LIF-OSM.LIF and OSM gene could be detected in feeder layer cells which infected by Ad-LIF-OSM.Exogenetic LIF and OSM have special effect in culturing HSC in vitro.Conclusion The adenoviral vector co-expressing LIF and OSM (Ad-LIF-OSM) were successfully constructed.Ad-LIF-OSM transgenic feeder cells can effectively proliferate umbilical cord blood CD34+ HSPC in vitro and delay it differentiate.

Role of stroma cell-derived factor-1 receptor in utero transplantation with hematopoietic stem/progenitor cells / 基础医学与临床

Objective To explore the effect of stroma cell-derived factor receptor CXCR4 on the homing of the hematopoietic stem/progenitor cells in utero transplantation. Methods CD34~+ cells were collected by Ficoil density gradient centrifugation and MiniMACS and then stimulated for 48 h by SCF and IL-6 cytokines prior to transplantation. CD184(CXCR4) expressions and transmigrate rates of the CD34~+ cells were analysed by flow cytometer. Cells pre-treated with different treatment were transplanted into the abdominal cavity of the fetal BALB/c mouse in the pregnant days 13～14. Human CD45 cells as the marker of graft were detected by flow cytometry after 1 month the fetus born. Results Expression changes of CD184 on CD34~+ cells were from 9. 58%±1. 56% to 19. 32%±3. 64% after SCF and IL-6 stimulation. The CD34~+/CXCR4~(high) cells exhibited significant increases in SDF-1 mediated chemotaxis compared with the CD34~+/CXCR4~(low) cells. Transmigration of CD34~+ /CXCR4~(high) was inhibited by pretreatment with an-tiCXCR4mAb and PTX. The positive rates of human CD45 cells detected in the fetal mouse were significantly higher in the SCF and IL-6 pretreatment group. This effects were significantly abrogated after the addition of antiCXCR4mAb or PTX. Conclusion Up-regulation of CXCR4 expression may be useful for improving hematopoietic stem/progenitor cells homing in utero transplantation. This homing process is mediated and depends on the CXCR4 receptors. The signal transduction is mediated by PTX-sensitive Gi protein.

Effect of feeder cells transduced with Ad-hLIF on the expansion of CD34+ cells in indirect co-culture / 中华微生物学和免疫学杂志

Objective To establish Ad-hLIF transgenic feeder cells for the expansion of umbilical cord blood CD34+ HSPC in vitro and study the SCID mice model of hematopoietic stem/progenitor cell (HSPC) transplantation. Methods The expression of objective gene in Ad-hLIF transgenic feeder cells was detected by RT-PCR and ELISA. The purity of umbilical cord blood CD34+ HSPC separated by magnetic-activated cell sorting(MACS) was detected by the flow cytometry. After expanded with various combinant of cytokines and transgenic feeder layer cells for 28 d, the quantity of mono-nuclear cell (MNC) and CD34+ cells rate was detected in different time. MNC after expansion stained by CFDA SE was injected to the sublethally irradiated SCID mice. Humanize gene Alu was detected by RT-PCR and fluorescence microscope. Results The green fluorescence was observed in the transgenic cells infected with 50MOI( multiplicity of infection) Ad-hLIF, and the objective gene was confirmed by RT-PCR and ELISA. The purity of umbilical cord blood CD34+ HSPC separated by MACS could reach 95.60% ±2.58%, Ad-hLIF transgenic feeder cells and various cytokines system increased MNC by 356.95±0.87 fold, and maximal expansion of CD34+ cells was observed during 0-14 d of culture, then down-expansion gradually. Four weeks after transplanted in SCID mice, fluorescently-labeled humanize cells still can be observed. The existence of the humanized gene Alu was confirmed by RT-PCR. Conclusion Ad-hLIF transgenic feeder cells can effectively proliferate umbilical cord blood CD34+ HSPC in vitro and delay it differentiate, what's more, it has high transplant efficacy and haematogenesis activity.

Effect and it's mechanism of microgravity on biological characteristics of hematopoietic stem/progenitor cells / 国际生物医学工程杂志

Hematopoietic stem/progenitor cells have the potential of self-renewal,proliferation and multidirectional differentiation,which maintain the normal haematopoiesis of bnmml body.Alterations in the number and function of mature blood cells in the peripheral blood commonly observed in humans exposed to microgravity (μ-g)are results of many reasons.The change of biological characteristic of hematopoietic stem/progenitor cells is one of the important ressons.Migration,proliferation,and differentiation of hematopoietic stem/progenitor cells under microgravity are summarized in this article.

Role of stroma cell-derived factor-1 receptor in utero transplantation with hematopoietic stem/progenitor cells / 基础医学与临床

Objective To explore the effect of stroma cell-derived factor receptor CXCR4 on the homing of the hematopoietic stem/progenitor cells in utero transplantation. Methods CD34+ cells were collected by Ficoll density gradient centrifugation and MiniMACS and then stimulated for 48 h by SCF and IL-6 cytokines prior to transplantation. CD184(CXCR4) expressions and transmigrate rates of the CD34+ cells were analysed by flow cytometer. Cells pretreated with different treatment were transplanted into the abdominal cavity of the fetal BALB/c mouse in the pregnant days 13～14. Human CD45 cells as the marker of graft were detected by flow cytometry after 1 month the fetus born. Results Expression changes of CD184 on CD34+ cells were from 9.58%?1.56% to 19.32%?3.64% after SCF and IL-6 stimulation. The CD34+/CXCR4high cells exhibited significant increases in SDF-1 mediated chemotaxis compared with the CD34+/CXCR4low cells. Transmigration of CD34+/CXCR4high was inhibited by pretreatment with antiCXCR4mAb and PTX. The positive rates of human CD45 cells detected in the fetal mouse were significantly higher in the SCF and IL-6 pretreatment group. This effects were significantly abrogated after the addition of antiCXCR4mAbor PTX. Conclusion Up-regulation of CXCR4 expression may be useful for improving hematopoietic stem/progenitor cells homing in utero transplantation. This homing process is mediated and depends on the CXCR4 receptors. The signal transduction is mediated by PTX-sensitive Gi protein.

Effect of Angiotensin Ⅱ on Cord Blood CD34+ Cells Expansion in vitro / 华中科技大学学报（医学）（英德文版）

In order to investigate the influence of angiotensin Ⅱ on hematopoietic system, CD34+cells in cord blood were purified, and the effects of angiotensin Ⅱ in combination with various cytokines on their growth and differentiation were studied by cell culture in vitro. It was found that angiotensin Ⅱ in suspending medium could stimulate both BFU-E and CFU-GM expansion. The number of BFU-E and CFU-GM was increased with the increases of angiotensin Ⅱ concentrations during a certain range. In addition, the expansion fold of CFU-GM was increased from 2.3±0.8 times to 7.8±2.3 times when angiotensin Ⅱ was added in the presence of SCF+G-CSF+GM-CSF+IL-3 cytokines mixture. Similarly, the expansion fold of BFU-E was increased from 3.1 ±1.8 times to 9.2±2.3 times with angiotensin Ⅱ in the presence of SCF+EPO+TPO+IL-3. In the semi-solid medium, angiotensin Ⅱ could stimulate CFU-GM expansion but had no effect on the growth of BFU-E. In conclusion, angiotensin Ⅱ had some stimulating effects on cord blood hematopoietic progenitors expansion in vitro in the presence of other cytokines.

Effects of Rosa roxburghii Tratt extract-CL1 on gastric carcinoma SGC-7901 cells growth and human umbilical cord CD34~+ cells proliferation and differentiation / 中国临床药理学与治疗学

(0.05)) CONCLUSION: CL1 has inhibitory effect on growth of SGC-7901 cells in vitro,but does not affect proliferation of CD34~+ and differentiation of CD34~+ haematopoietic stem/progenitor cells to granulocyte and monocytes.This demonstrates that CL1 has anticancer effect,but does not affect the proliferation and differentiation of haematopoietic stem/progenitor cell to granulocytes and monocytes.It may not cause obvious haematopoietic depression.

The effect of mobilization of ginseng polysaccharide on murine hematopoietic stem/progenitor cell / 重庆医科大学学报

Objective:To study the mobilizable effect of ginseng polysaccharide(GPS)on murine hematopoietic stem/ progenitor cells and provide experimental evidences for mobilizable preparation of hematopoietic stem cell from plant polysaccharide.Methods:The changes of the numbers of WBC and MNC,the percentage of CD34+ cell and the yields of CFU-Mix in peripheral blood were examined by means of WBC and MNC counts,immunocytochemistry,flow cytometry and hematopoietic cell culture in vitro.Results:4 hours after injection of GPS into mice with a dosage of 2 mg/kg,the numbers of WBC and MNC reached the maximum,which were 3 times and 3.5 times that of the NS group respectively.The percentage of CD34+ cell and the yields of CFU-Mix in vitro in peripheral blood(0.0079?0.0011 and(25.0?9.1)cfu/2?105MNC respectively)after the mobilization by GPS were obviously higher than those of the NS group.The effect of mobilization by combination of GPS and G-CSF was much better than that mobilized by single administration of GPS.Conclusion:GPS alone or in combination with G-CSF could significantly mobilize murine hematopoietic stem/progenitor cells from bone marrow into peripheral blood.

Study on hematopoietic reconstruction for bone marrow depression mice with the transplantation of mobilized peripheral blood stem/proginiter cells by ginseng polysaccharide / 重庆医科大学学报

Objective:To study the hematopoietic reconstruction for bone marrow depression mice with mobilized peripheral blood stem/proginiter cells by ginseng polysaccharide.Methods: Establish hematopoiesis failure model of mouse and transplant murine peripheral blood mononuclear cells mobilized by GPS.To observe the survival time,WBC,the weight of spleen,the number of CFU-S of recipient mice and chromosome chimerism.Results: After PBMNCs(1?105)mobilized by GPS from mice(male) were injected to the lethality irradiated mice,it can reduce the time of WBC recovery obviously;prolong the time of murine survival,increase the number of WBC of the recipient mice;it can also increase the number of CFU-S,the weight of spleen;Evaluating the Y chromosome by PCR,the result showed that 581bp Y chromosome sequence was examined in peripheral blood of the recipient mice.Conclusion: There are a lot of hematopoietic stem/ proginiter cells in peripheral blood of the mice mobilized by GPS,so it can obviously reconstruct the hematopoiesis of the bone marrow depression mice by transplantation.

Gene HSPC016 Expressed in Aggregated Human Dermal Papilla Cells of Hair Follicles / 中华皮肤科杂志

Objective To identify the relationship between expression of hematopoeitic stem/progenitor cell(HSPC)-related gene HSPC016 and aggregative behavior of the dermal papilla cells of hair follicles. Methods The aggregated human dermal papilla cells, non-aggregated human dermal papilla cells and the human dermal fibroblasts were used in this study. Expression of HSPC016 mRNA was investigated in the three cell groups by intracellular mRNA hybridization in situ and RT-PCR. Results By in situ hybridization, it was shown that gene HSPC016 specifically expressed in the aggregated dermal papilla cells, but not in the non-aggregated human dermal papilla cells and human dermal fibroblasts. A 200bp fragment of target cDNA was amplified from RNAs of the aggregated human dermal papilla cells by RT-PCR, but could not from RNAs of other two cell lines. Conclusions Gene HSPC016 was specifically expressed in the aggregated dermal papilla cells, and expression of HSPC016 might be related to the differentiation and functions of dermal papilla cells.