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6. Materials And Methods

6.1. Mesenchymal Stem Cells (MSCs) isolation and expansion

Mice were sacrificed by cervical dislocation before extracting bones (both tibias

and femurs). MSCs were isolated from bone marrow (BM), flushed out from

tibias and femurs.

BM was seeded in Complete Medium, composed by MesenCult Basal Medium

supplemented with 20% Mesenchymal Mouse Stimulatory Supplement

(StemCell Technologies) and 1% Pen-Strept (Life Technologies). Cells were

seeded and grown at 37°C in humidified atmosphere at 5% CO

2

.

MSCs adhere to plastic, and such criterion was used to distinguish them from

the BM hematopoietic component, which grows in suspension. In addition, the

use of MesenCult medium ensured a proper selection of the MSC component,

since it specifically support MSCs growth. Medium was changed every 3 days.

Once adherent cells reached confluence, they were removed from the culture

dishes by using Trypsin 1x (Life Technoligies) for 6 minutes, and subsequently

spun at 1250 rpm for 5 minutes.

Cells were resuspended in Complete Medium, counted on a Burker chamber

and subsequently reseeded at 2x10^4 cells/cm

2

(passage 1, p1).

A second passage in culture was adopted to further eliminate the hematopoietic

component, and to expand further the MSC population, in order to obtain a

sufficient number of cells to perform the subsequent experiments. All

experiments were started at passage 2 (p2).

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6.1.1. Adipogenic differentiation

MSCs were seeded at p2 at 2x10^4 cells/cm

2

. Once cells reached 80%

confluence, the Complete Medium originally used to maintain their

proliferation was replaced with Adipogenic Induction Medium, composed of

MesenCult Basal Medium supplemented with 20% Adipogenic Stimulatory

Supplement (StemCell Technologies) and 1% Pen-Strept (Life Technologies).

Cells were collected at different time points during adipogenic differentiation

(after 1, 2, 3, 5, 7 and 14 days), centrifuged at 4500 rpm for 5 minutes and their

corresponding pellets stored at -80°C.

6.1.2. Osteogenic differentiation

MSCs were seeded at p2 at 2x10^4 cells/cm

2

. Once cells reached 100%

confluence, the Complete Medium initially used to maintain their proliferation

was replaced with Osteogenic Induction Medium, composed of MesenCult

Basal Medium supplemented with 20% Osteogenic Stimulatory Supplement

(StemCell Technologies) and 1% Pen-Strept (Life Technologies).

Cells were collected at different time points during osteogenic differentiation

(after 1, 2, 3, 5, 7, 14 and 21 days), centrifuged at 4500 rpm for 5 minutes and

their pellets stored at -80°C.

6.1.3. Cytochemical Staining

At the end of adipogenic and osteogenic differentiation, cells were stained to

evaluate the efficiency of their induced differentiation.

Oil Red O staining was performed on terminally differentiated adipocytes. Oil

Red O labels lipid droplets present in the cytoplasm of mature adipocytes.

A staining stock solution was prepared by dissolving 0,25g Oil Red O (Sigma)

in 50ml isopropyl alcohol. A fresh working solution was prepared each time, by

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adding PBS 1x to the stock solution (3 parts of Oil Red stock + 2 parts of PBS

1x).

Alizarin Red S staining was performed on terminally differentiated osteoblasts.

Alizarin Red S dyes the calcium phosphate secreted by mature osteoblasts

during bone mineralization.

A stock/working solution was prepared by dissolving 0,5g Alizarin Red S

(Sigma) in 50 ml H

2

O, and pH was brought to 4.1-4.3.

Each working solution was filtered through 0.22µm filters before use in order to

remove debris.

Cells were fixed with 4% formaldehyde for 20 minutes at Room Temperature

(RT), stained for 15 minutes in the dark, and subsequently washed with distilled

water.

6.2. RNA extraction

RNA was extracted from frozen cell pellets by using the NucleoSpin® RNA

XS kit (Macherey-Nagel), which allows for the isolation of highly concentrated

and pure RNA from small samples. This kit uses silica membrane technology.

Briefly, cells are lysed by incubation in a solution containing large amounts of

chaotropic ions. The lysis buffer immediately inactivates the RNases virtually

present in every biological sample, and creates the appropriate binding

conditions to favour absorption of RNA to the silica membrane. After lysis,

homogenization and reduction of viscosity are achieved by filtration with

NucleoSpin® Filter units. Residual genomic DNA is efficiently eliminated by

digestion with rDNase, provided by the kit. Each step of the RNA extraction

was performed according to the manufacture’s protocol.

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RNA concentration was measured with NanoVue Plus Spectrophotometer.

Briefly,

1

µl

of each sample was exposed to ultraviolet light at 260 nm, and a

photo-detector measured the light passing through the sample. The more light

absorbed by the sample, the higher the nucleic acid concentration.

It is common

for nucleic acid samples to be contaminated with other molecules (i.e. proteins

or organic compounds). The ratio of the absorbance at 260 and 280nm (A

260/280

)

is used to assess the purity of nucleic acids from proteins, whereas A

260/230

is

used to assess the purity from carbohydrates and phenols (solvents). We always

utilized RNA of the highest purity (with reading of A

260/280

=1,9 and A

260/230

=

2).

6.3. cDNA sytnthesis

Reverse transcription of RNA was performed using the QuantiTect Reverse

Transcription Kit (Qiagen), accordingly to manufacture’s protocol. Purified

RNA was briefly incubated in gDNA Wipeout Buffer to effectively remove

contaminating genomic DNA. The RNA sample was then used directly in a

reverse transcription reaction, using a master mix composed of Quantiscript

Reverse Transcriptase, Quantiscript RT Buffer, and RT Primer Mix. The entire

reaction was carried out at 42°C and it was subsequently inactivated at 95°C.

6.4. Real Time qPCR

Real Time qPCR was performed by using the QuantiTect SYBR Green PCR

Kits, which contains a ready-to-use master mix, composed of HotStart Taq

DNA Polymerase, SYBR Green PCR Buffer, SYBR Green I, and dNTPs. The

fluorescent dye SYBR Green I intercalates in the minor groove of the double

DNA strand. The stronger the fluorescence released, the higher the DNA

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quantity. Abalanced combination of K

+

and NH

4+

ions in the PCR buffer

promotes specific primer annealing and enables high PCR specificity and

sensitivity. In addition,HotStarTaq DNA Polymerase provides a stringent hot

start, preventing the formation of non-specific products.

Samples were prepared in 15 µl total volume, containing SyBR Green I Master

mix 1X, forward and reverse primers (0,3µM) specific for each gene. Primers

were designed and verified by using the Beacon Designer 5.0 and the Primer3

Software, respectively.

Real Time qPCR reaction was run on a Rotor Gene 3000 (Corbett). Data were

normalized to the levels of the housekeeping gene Hprt.

6.5. Protein Extraction

Protein extraction was performed by using a freshly prepared lysis buffer

working solution, composed of RIPA Buffer stock solution, 1%NP40 (Igepal

CA-630), 1 mM PMSF (

PhenylmethylsulfonylFluoride)

, 1% Protease Inhibitor

(ProteaseInhibitor Cocktail Tablets, cOmplete Mini, Roche). RIPA Stock

Buffer is composed of H

2

O, 50mM Tris HCL, 150 mM NaCl, 1mM EDTA, 1%

SDS, 0,5% DOC, and stored at 4°C. Cell pellets were resuspended on ice in 50

µl lysis buffer working solution and incubated on ice for 30 minutes. After

incubation cells were sonicated 3 times (10 seconds @ power 7), with Misonix

Microson 22000 and centrifuged 10 minutes at 6000 rcf at 4°C. Supernatants,

which contain the protein extracts, were transferred to clean tubes, and stored at

-80°C.

Protein concentration was evaluated by using the Micro BCA

TM

Protein Assay

kit (ThermoScientific), according to manufacture’s datasheet.

The Thermo Scientific Pierce Micro BCA Protein Assay can be used on a

spectrophotometer (A 562nm) to measure total protein concentration of diluted

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protein solutions (ranging from 0,5 to 20µg/mL).

6.6. Western Blot

After protein extraction 30µg of the protein homogenates were mixed with

Loading Buffer (Loading Buffer 4x was composed of Tris-HCl pH 6.8,

β-mercaptoethanol, SDS, Glycerol, bromophenol blue, Milli-Q-H

2

O) and

incubated at 99°C for 10 minutes. This incubation allows for protein

denaturation, which is necessary to obtain a correct separation by

electrophoresis. Proteic lysates were then separated by SDS-PAGE (Sodium

Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) and transferred to PVDF

membranes (at 200mA for 2 hours). Upon incubation with primary and

secondary antibodies, immunoreactive bands were detected by ECL reaction

(Millipore), according to manufacturer’s datasheet.

-The primary antibodies utilized in our study were:

Mouse anti-Prep1 (Santa Cruz Biotechnology sc-25282, 200µg/ml), dilution

1:1000.

Rabbit anti-Pbx1 (Santa Cruz Biotechnology, sc-889, 200µg/ml), dilution

1:500.

Goat anti-Meis1/2 (Santa Cruz Biotechnology, sc-10599, 200µg/ml), dilution

1:500.

Rabbit anti-Cytoskeletal Actin (Bethyl Laboratories A300-485A, 1mg/ml),

dilution 1:10000.

-the secondary antibodies utilized in our study were:

Goat Anti-Mouse HRP (Santa Cruz Biotechnology, sc-2005, 200µg/0,5ml),

dilution 1:1000

Goat Anti-Rabbit HRP (Santa Cruz Biotechnology, sc-2004, 400µg/ml),

dilution 1:1500

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Donkey Anti-Goat HRP (Santa Cruz Biotechnology, sc-2033, 200µg/0,5ml),

dilution 1:2000

Upon development of the films, pixel intensity of the resulting bands was

quantified by using ImageJ Software.

6.7. Flow Cytometry Analysis

Flow cytometry analysis was performed on a FACSCalibur

TM

flow cytometer.

Cells were resuspended in staining solution (PBS 1X, 1% FBS (Fetal Bovine

Serum) and stained with Phycoerythrin (PE) conjugated anti-mouse Kit-PE

(1:10) (Anti-Mouse CD117-PE 0,2mg/ml eBioscience, #12-1171)

Cells were stained for 30 minutes at 4°C in the dark, then washed twice with

PBS 1x and analyzed by flow cytometry.

Results were analyzed by using FlowJo Software.

6.8. Detection of apoptosis

In order to quantify apoptotic cells we took advantage of two different

tecniques, namely the TUNEL assay and Annexin V- PI staining (FACS

analysis), as explained below.

6.8.1. TUNEL assay:

The In Situ Cell Death Detection Kit Fluorescein (Roche) is based on the

detection of single- and double-stranded DNA breaks that occur at the early

stages of apoptosis. Apoptotic cells are fixed and permeabilized. Subsequently,

cells are incubated with the TUNEL reaction mixture that contains TdT and

fluorescein-dUTP. During this incubation period, TdT catalyzes the addition of

fluorescein-dUTP to the free 3'-OH groups of single- and double-stranded

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DNA. After washing, the label incorporated at the damaged sites of the DNA is

visualized by fluorescence microscopy.

6.8.2. Annexin V and PI staining

Apoptosis was detect by using a detection Kit purchased from BD Pharmingen

(FITC Annexin V Apoptosis Kit). In apoptotic cells, the membrane

phospholipid phosphatidylserine (PS) is translocated from the inner to the outer

leaflet of the plasma membrane, thereby exposing PS to the external cellular

environment. Annexin V (conjugated to the fluorochromes FITC) is a 35-36

kDa Ca2

+

-dependent phospholipid-binding protein with high affinity to PS,

binding therefore cells with exposed PS, thus constituting a sensitive probe for

flow cytometric analysis of apoptotic cells. Briefly, cells are incubated for 15

minutes in the dark at room temperature with the staining solution (Binding

Buffer 1X, FITC Annexin V and Propidium Iodide (PI)) and then analyzed on a

cytometer (FACSCalibur

TM

). FITC Annexin V stains both early apoptotic and

completely apoptotic cells. Viable cells with intact membranes exclude PI,

whereas the membranes of dead and damaged cells are permeable to PI. Cells

that are considered viable are FITC Annexin V and PI negative; cells that are in

early apoptosis are Annexin V positive and PI negative; and cells that are in late

apoptosis or already dead are double positive for Annexin V and PI.

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